Derivatives of 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine

ABSTRACT

The instant disclosure relates to (among other things) compounds that are derivatives of 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine. The compounds provided possess unique effects and differences over other phenyltriazines known in the art.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 35 U.S.C § 371 application of InternationalApplication No. PCT/IN2014/000789, filed Dec. 19, 2014, designating theUnited States, which claims the benefit of priority to IndianProvisional Patent Application No. 2966/DEL/2014, filed Oct. 17, 2014;Indian Provisional Patent Application No. 1799/DEL/2014, filed Jul. 3,2014; and Indian Provisional Patent Application No. 3732/DEL/2013, filedDec. 21, 2013, each of which is hereby incorporated by reference intheir entireties.

FIELD

This disclosure comprises (among other things) derivatives of6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine that possess uniqueproperties. The derivatives of6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine described herein relate toand/or have application(s) in (among others) the fields of drugdiscovery, pharmacotherapy, physiology, and organic chemistry.

BACKGROUND

As the name suggests, phenyltriazines are a class of molecules thatcontain both a phenyl group and a triazine group. The phenyltriazineclass of molecules has a variety of activities and uses. For example,one of the most well-known members of the phenyltriazines in the fieldof pharmacology is lamotrigine[3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine], which has beenshown to be useful for treating patients suffering from epileptic andbipolar disorders. Other phenyltriazines have been used as UV absorbers.See U.S. Pat. No. 6,916,867. Still other phenyltriazines have been shownto have activity against malarial infections. See U.S. Pat. No.3,637,688. Thus, in view of their myriad activities and uses,phenyltriazines represent an important class of molecules.

In view of the above, there remains a need to continue to identify newphenyltriazines, with the aim of finding new uses within this class ofactive molecules or improving the properties of currently knownphenyltriazines.

By way of example, individuals being treated with the phenyltriazine,lamotrigine, may experience many side effects, including lifethreatening skin reactions, including Stevens-Johnson syndrome, toxicepidermal necrolysis, headaches, dizziness and insomnia. Other sideeffects may include acne and skin irritation, vivid dreams ornightmares, night sweats, body aches and cramps, muscle aches, drymouth, fatigue, memory problems, cognitive problems, irritability,weight changes, hair loss, changes in libido, frequent urination, andnausea. Therefore, pharmacotherapy with such phenyltriazine would benotably improved if these and/or other adverse or side effectsassociated with their use could be lessened or if their pharmacologycould be improved. Thus, there is a large unmet need for additionalnovel phenyltriazine compounds having beneficial and or improvedproperties over lamotrigine.

The present disclosure seeks to address these and other needs in theart.

SUMMARY

In one aspect, provided herein are derivatives of6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine. The compounds providedherein each possess an N-bonded substituent at the 3-position of thetriazine ring and an amino (—NH₂) group at the 5-position of thetriazine ring, based upon the numbering scheme provided below. TheN-bonded substituent is an amino nitrogen covalently attached to the3-carbon of the triazine ring, where the amino nitrogen may be comprisedwithin a substituted acyclic amino moiety, or may form part of asubstituted or unsubstituted nitrogen-containing heterocycle such as asubstituted or unsubstituted piperazine moiety, a substituted orunsubstituted piperidine, a substituted or an unsubstituted pyrrolidinemoiety, a substituted or an unsubstituted azetidine, or a substituted oran unsubstituted diazetidine, where any of the foregoingnitrogen-containing heterocycles may also form part of a bi- or atricylic ring structure. Generally, the compounds provided herein havethe following general structure:

The amino linked moiety is attached to the 3-carbon of the triazine ringby an amino-linkage, where the amino group may be a primary amino group(—NH₂), or may be a secondary or a tertiary amino group (comprising oneor no hydrogens, respectively). The amino group is generally but notnecessarily a substituted amino group, i.e., having one or no hydrogens.The amino group may, for example, be substituted with an alkyl chain(s)that is linear or branched, and/or may comprise an oligomeric ethyleneoxide chain, both of which may be further substituted. In one or moreembodiments, substituents include one or more functional groups selectedfrom, for example, oxygen (ether), amino, hydroxyl, carboxyl, carbonyl,sulfonyl, aldehyde, alkylsulfone, tetrazole, carbonyl, oxetane,carbonate, alkyl ester, sulfoxide, halo, amido, sulfonamide, cycloalkyl,heterocyclyl, —CF₃, —CF₂H, CFH₂, and the like.

In some embodiments, the amino group linked to the 3-carbon of thetriazine ring may also be comprised within a ring structure. The aminogroup may, for example, be comprised within a substituted orunsubstituted piperazine moiety, or within a substituted orunsubstituted pyrrolidine moiety, or within a substituted orunsubstituted piperidine, or within a substituted or unsubstitutedazetidine, or within a substituted or unsubstituted diazetidine, and thelike, or may be comprised within a bicyclic ring comprising one of theforegoing heterocycles, such as a hexahydropyrazino-oxazin-one, orhexahydropyrazino-oxazine, diazaspiro-octane, diazaspiro-nonane, and thelike. Substituted ring structures include rings as described abovesubstituted with an alkyl chain that is linear or branched, and/or withan oligomeric ethylene oxide chain (that may comprise a substituent onan alkyl chain) both of which may be further substituted. In one or moreembodiments, substituents include one or more functional groups selectedfrom, for example, oxygen (ether), amino, hydroxyl, carboxyl, carbonyl,sulfonyl, aldehyde, alkylsulfone, tetrazole, carbonyl, oxetane,carbonate, alkyl ester, sulfoxide, halo, amido, sulfonamide, cycloalkyl,heterocyclyl, —CF₃, —CF₂H, CFH₂, and the like.

In some embodiments, the dichlorophenyl ring may possess an additionalsubstituent at any one of positions 4, 5 or 6, where the substituent isselected from halo, hydroxyl, and oligomeric ethylene oxide(—OCH₂CH₂)_(n)OR, where n is in a range from 1-7 and R is selected fromH, -lower alkyl, preferably methyl, and fluoro-substituted methyl (e.g.,—CF₃, —CHF₂, —CH₂F).

In one or more embodiments, derivatives of6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine of the following structureare provided:

where M is a substituted amino moiety —NR₆R₇, wherein

R₆ and R₇ are each independently selected from the group consisting ofH, lower alkyl, —(CH₂CH₂O)_(m)R₈, —CH₂CH₂-(3-7 memberedheterocycloalkyl), —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CR₁₁R₁₂CH₂OH,—CR₁₁R₁₂CH₂O(CH₂CH₂O)₁₋₇R₁₀, —CH—[CH₂OH]₂; —CCH₃(CH₂OH)₂,—CCH₃(CH₂OH)CH₂O(CH₂CH₂O)₁₋₇R₁₀, alkylamino, hydroxyalkylamino,—CH₂CH₂NCH₃C(O)CH₂(OCH₂CH₂)₁₋₇R₁₀, —CH₂CH₂NCH₃C(O)CH₂OCH₂C(O)NH₂,—CH₂CH₂NCH₃(CH₂CH₂O)₁₋₇R₁₀, —CR₁₁R₁₂CH(O), —CR₁₁R₁₂(CH₂)₁ or₂SO₂—CH₂CH₂O)₁₋₇R₁₀, —CCH₃(CH₂OCH₂CH₂OCH₃)₂, —OCH₂CR₉HCH₂OR₁₀

—CH₂CR₉HCH₂NHC(O)CH₂O(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂NHC(O)CH₂OCH₂C(O)NH₂,and —(OCH₂CH₂)_(m)OR₁₀, with the proviso that R₆ and R₇ are not both H,

or wherein R₆ and R₇ taken together with N form a heterocycloalkyl ringselected from piperazine, piperidine, and azetidine, which mayoptionally form part of a bicyclic ring structure, where theheterocycloalkyl ring or bicyclic ring is either unsubstituted or issubstituted with a group selected from lower alkyl, —(CH₂CH₂O)_(m)R₈,—C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,

—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CH₂CH₂SO₂CH₃,—NR₉(CH₂CH₂O)_(m)R₁₀, tetra-hydro-2H-pyranyl, piperidinyl, —CH₂OH,—CH₂R₁₀, amino, —CHCH₃CH₂OH, hydroxyl, —CR₁₁R₁₂CH₂OH, —C(O)OCH₃, —CF₃,—CH₂C(OH)CF₃, —CH₂OCH₂—C₆H₅F, and—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₃,

m is in a range from 0-29,

R₈ is selected from H, C1-C6 alkyl, fluoro-substituted methyl (e.g.,—CF₃, —CF₂H, or —CFH₂), —CH₂COOR₁₀, —CH₂COCH₃, 3-7 memberedheterocycloalkyl, 3-7 membered heteroaryl, heteroarylalkyl, —C(O)OCH₃,C1-C6 alkyl substituted with one or more of hydroxyl, amino, alkylamino,amido, alkylamide, amidoalkylamine, acylamino, carboxyalkylamino,sulfonamide, sulfone, alkylsulfone, alkoxyalkyl sulfone,alkyloxyalklsulfoxide, 3-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, carboxyl, —NHCH₂CH₂OCH₃, —NHCHR₉COOR₁₁; and—CH—[CH₂O—(CH₂CH₂O)₂₋₈CH₃]₂;

R₉ is H, lower alkyl, hydroxyl,

R₁₀ is selected from H, lower alkyl and fluoro-substituted methyl,

R₁₁ and R₁₂ are each independently selected from H and lower alkyl,

R₁₃ is cyclopropyl or cyclobutyl, and

W is an optional substituent (where the subscript zero indicates itsabsence and the subscript 1 indicates its presence) selected from halo,hydroxyl, and oligomeric ethylene oxide (—OCH₂CH₂)_(n)OR, where n rangesfrom 1-7 and R is selected from H, -lower alkyl, preferably methyl, andfluoro-substituted methyl (e.g., —CF₃, —CHF₂, —CH₂F). In someembodiments, W is fluoro. In some additional embodiments, W is a fluorogroup positioned at the 5-position of the phenyl ring, based upon thenumbering provided herein.

In one or more embodiments, when R₆ is H and W is absent, R₇ does notequal —(CH₂CH₂O)₂₋₁₁ CH₃.

In one or more embodiments, R₆ is H.

In some embodiments, R₆ and R₇ are each independently selected from thegroup consisting of H, lower alkyl, —(CH₂CH₂O)_(m)R₈, —CH₂CH₂-(3-7membered heterocycloalkyl), —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CR₁₁R₁₂CH₂OH,—CR₁₁R₁₂CH₂O(CH₂CH₂O)₁₋₇R₁₀, —CH—[CH₂OH]₂; —CCH₃(CH₂OH)₂,—CCH₃(CH₂OH)CH₂O(CH₂CH₂O)₁₋₇R₁₀, alkylamino, hydroxyalkylamino,—CH₂CH₂NCH₃C(O)CH₂(OCH₂CH₂)₁₋₇R₁₀, —CH₂CH₂NCH₃C(O)CH₂OCH₂C(O)NH₂,—CH₂CH₂NCH₃(CH₂CH₂O)₁₋₇R₁₀, —CR₁₁R₁₂CH(O), —CR₁₁R₁₂(CH₂)₁ or₂SO₂—CH₂CH₂O)₁₋₇R₁₀, —CCH₃(CH₂OCH₂CH₂OCH₃)₂, —OCH₂CR₉HCH₂OR₁₀—CH₂CR₉HCH₂NHC(O)CH₂O(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂NHC(O)CH₂OCH₂C(O)NH₂,and —(OCH₂CH₂)_(m)OR₁₀, where variables possess the values providedabove, and with the proviso that R₆ and R₇ are not both H.

In yet some further embodiments, R₆ is H and R₇ is selected from thegroup consisting of H, lower alkyl, —(CH₂CH₂O)_(m)R₈, —CH₂CH₂-(3-7membered heterocycloalkyl), —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CR₁₁R₁₂CH₂OH,—CR₁₁R₁₂CH₂O(CH₂CH₂O)₁₋₇R₁₀, —CH—[CH₂OH]₂; —CCH₃(CH₂OH)₂,—CCH₃(CH₂OH)CH₂O(CH₂CH₂O)₁₋₇R₁₀, alkylamino, hydroxyalkylamino,—CH₂CH₂NCH₃C(O)CH₂(OCH₂CH₂)₁₋₇R₁₀, —CH₂CH₂NCH₃C(O)CH₂OCH₂C(O)NH₂,—CH₂CH₂NCH₃(CH₂CH₂O)₁₋₇R₁₀, —CR₁₁R₁₂CH(O), —CR₁₁R₁₂(CH₂)₁ or₂SO₂—CH₂CH₂O)₁₋₇R₁₀, —CCH₃(CH₂OCH₂CH₂OCH₃)₂, —OCH₂CR₉HCH₂OR₁₀—CH₂CR₉HCH₂NHC(O)CH₂O(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂NHC(O)CH₂OCH₂C(O)NH₂,and —(OCH₂CH₂)_(m)OR₁₀, where variables possess the values providedabove.

In some preferred embodiments, m is selected from 0, 1, 2, 3, 4, 5, 6,and 7.

In some additional embodiments, R₆ and R₇ taken together with N form aheterocycloalkyl ring selected from piperazine, piperidine, andazetidine, which may optionally form part of a bicyclic ring structure,where the heterocycloalkyl ring or bicyclic ring is either unsubstitutedor is substituted with a group selected from lower alkyl,—(CH₂CH₂O)_(m)R₈, —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CH₂CH₂SO₂CH₃,—NR₉(CH₂CH₂O)_(m)R₁₀, tetra-hydro-2H-pyranyl, piperidinyl, —CH₂OH,—CH₂R₁₀, amino, —CHCH₃CH₂OH, hydroxyl, —CR₁₁R₁₂CH₂OH, —C(O)OCH₃, —CF₃,—CH₂C(OH)CF₃, —CH₂OCH₂—C₆H₅F, and—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₃, where variables such as m, R₈,R₉, R₁₀, R₁₁, R₁₂, and R₁₃ possess the values provided above.

In one or more embodiments, R₆ is H and R₇ is —(CH₂CH₂O)_(m)R₈, where mis selected from 1, 2, 3, 4, 5, 6, and 7, and R₈ is selected from H,methyl, isopropyl, fluoro-substituted methyl, carboxyl, and 3-7 memberedheterocycloalkyl. In one or more related embodiments, the 3-7 memberedring heterocycloalkyl is selected from tetrazole, oxetane andpiperazine.

In some embodiments, R₆ and R₇ taken together with N form aheterocycloalkyl ring selected from piperazine, piperidine, andazetidine. In some particular embodiments, R₆ and R₇ taken together withN form an unsubstituted or a substituted piperazine. Exemplarysubstituted piperazines include those having a N-substituent selectedfrom —(CH₂CH₂O)₁₋₇C1-C6 alkyl or fluoro-substituted methyl,—(CH₂CH₂O)₁₋₇CH₂CH₂NHSO₂CH₃,

—C(O)CH₂O(CH₂CH₂O)₁₋₇CH₃, —CH₂CHOHCH₂OCF₃,—CH₂CHOHCH₂OCH₂CF₃—CH₂CHOHCH₂OCH₃, —CH₂OH, —(CH₂CH₂O)₂OH, —CH₂CH₂SO₂CH₃,—CH₂CH₂OCH₂COOH, —CH₂CH₂OCH₂COOC(CH₃)₃, —CH₂CH(OH)CH₂OH,—C(CH₃)₂CH₂OCH₂CH₂OH,

—CH₂CF₃, —CHCH₃CH₂OH, —C(CH₃)₂CH₂OH, and —CH₂CH(OH)CH₂Cl. Exemplarycompounds wherein R₆ and R₇ taken together with N form an unsubstitutedor a substituted piperazine include compounds 92, 103, 104, 105, 106,113, 120, 121, 122, 123, 96, 97, 87, 89, 88, 90, 94, 207, 98, 13, 136,137, 208, 124, 27, 200, 201, 202, 203, 204, 138, 139, 140, 55, 73, 78,80, and 83.

In some additional embodiments, R₆ and R₇ taken together with N form aring selected from substituted pyrrolidine, substituted piperazine, andsubstituted piperazine forming part of a bicyclic ring system, e.g.,tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (as in compound 128),tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (as in compound 127), andhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (as in compound 130), andazetidine.

In some particular embodiments, the compound is selected from the groupconsisting of: (2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97),(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol-2HCl(Compound 95),(R)-1-((1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75), 3-N-(3-hydroxyazetin-1-yl) lamotrigine (Compound 129),1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27),(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)lamotrigine di HCl (Compound 120), and(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130).

In one or more embodiments, derivatives of6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine of the following structureare provided:

wherein:

A is selected from the group consisting of

G is selected from the group consisting of ˜O˜, ˜CH₂˜,

p is 0 or 1 (where a value of 0 indicates the absence of oxygen and avalue of 1 indicates its presence); and

J is selected from the group consisting of ˜CH(OH)CH₂OH, ˜CH(OH)CH₂OCH₃,˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜CH₂OCH₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂,˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹, where R¹ equals methyl orfluoro-substituted methyl (e.g., —CF₃, —CF₂H, or —CFH₂), ˜CH₂OCH₂CH₃,˜CH₂OCH(CH₃)₂,

and ˜OCH₂C(OH)HCH₂OCH₃,and pharmaceutically acceptable salts thereof.

In one or more embodiments of formula (I), G is

where G is selected from

In one or more additional embodiments, when J is ˜(OCH₂CH₂)₀₋₂₉OR¹, J isfurther selected from ˜OR¹ and ˜(OCH₂CH₂)₁₋₁₀OR¹.

In yet one or more further embodiments, when J is ˜(OCH₂CH₂)₀₋₂₉OR¹, Jis selected from ˜(OCH₂CH₂)OR¹, ˜(OCH₂CH₂)₂OR¹, ˜(OCH₂CH₂)₃OR¹,˜(OCH₂CH₂)₄OR¹, ˜(OCH₂CH₂)₅OR¹, ˜(OCH₂CH₂)₆OR¹, ˜(OCH₂CH₂)₆OR¹,˜(OCH₂CH₂)₈OR¹, ˜(OCH₂CH₂)₉OR¹, and ˜(OCH₂CH₂)₁₀OR¹.

In one or more further embodiments, compounds of the following structureare provided:

wherein (n) is an integer of 1 to 30, and pharmaceutically acceptablesalts thereof. Compounds in accordance with Formula II fall withinFormula I above where G is ˜CH₂˜, p equals zero, and J is˜(OCH₂CH₂)₁₋₂₉OR¹, where R¹ is —CF₃, and the number of ethylene oxidesubunits is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29.

In one or more embodiments, a compound having the following formula isprovided:

In the compound above, in reference to Formula I, G is

p is zero, and J is ˜OH.

In yet one or more additional embodiments, a compound in accordance withthe following structure is provided, where the substituent covalentlyattached to the 3-carbon of the triazine ring is a substitutedpyrrolidine moiety:

wherein R₂ is either H or ˜CH₂C(OH)CH₂OCH₃, and S₁ is an optionalsubstituent selected from ˜OCH₂CH₃ and

In one or more additional embodiments of the compound of formula (I), Ais

and the compound is selected from the group consisting of:

In yet one or more further embodiments of the compound of Formula (I), Ais

and the compound is selected from the group consisting of

In one or more additional embodiments, the6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine derivative compoundcomprises a substituted pyrrolidine at the 3-position of the triazinering and is selected from the group consisting of:

In one or more embodiments of the compound of Formula (I), A is

In one or more embodiments of the compound of Formula (I), A is

G is

p is 0, and J is selected from ˜CH(OH)CH₂OH, ˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH,˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂, ˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹,where R¹ equals methyl or fluoro-substituted methyl (e.g., —CF₃, —CF₂H,or —CFH₂), ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃.

In one or more additional embodiments of the compound of Formula (I), Ais

G is

p is 0, and J is selected from ˜OH, ˜OCH₂CH₂OH, ˜OCF₂H,˜OCH₂C(OH)HCH₂OCH₃ and ˜(OCH₂CH₂)₂OCF₃.

In one or more further embodiments, A is either

G is ˜CH₂˜, p is 0 or 1, and J is selected from ˜CH(OH)CH₂OH,˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂,˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹, where R¹ equals methyl orfluoro-substituted methyl (e.g., —CF₃, —CF₂H, or —CFH₂), ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃.

In yet one or more additional embodiments, A is either

G is ˜CH₂˜, p is 0, and J is selected from ˜OCH(CH₂OH)₂, ˜OCH(CH₂OCH₃)₂,˜OCF₃, ˜(OCH₂CH₂)OCF₃, ˜CH(OH)CH₂OCH₃, ˜CH₂OCH₂CH₃, ˜(OCH₂CH₂)₂OCF₂H.

In yet one or more additional embodiments, A is

G is ˜CH₂˜, p is 1, and J is ˜CH₂OCF₃.

In yet one or more further embodiments, A is

G is

p is 0, and J is selected from the group consisting of ˜CH(OH)CH₂OH,˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂,˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹, where R¹ equals methyl orfluoro-substituted methyl (e.g., —CF₃, —CF₂H, or —CFH₂), ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃.

In yet one or more further embodiments, A is

G is

p is 0, and J is selected from the group consisting of ˜OH,˜(OCH₂CH₂)OCH₃, and

In yet one or more additional embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more further embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more further embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more further embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more further embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more additional embodiments, the compound is

In yet one or more further embodiments, the compound is

In yet one or more further embodiments, the compound is

In yet one or more additional embodiments, the compound is

In some embodiments, the compound is selected from the group consistingof compounds 1-209. In one or more embodiments, provided is a compoundselected from the group consisting of Compounds 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 3, 38, 39, and 40.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 41, 42, 43, 44, 45, 46, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, and 60.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, and 80.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 and 100.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 101, 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, and120.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 121, 122, 123, 124, 125, 126,127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, and140.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 141, 142, 143, 144, 145, 146,147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, and160.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 161, 162, 163, 164, 165, 166,167, 168, 169, 170, 171, 172, 13, 174, 175, 176, 177, 178, 179, and 180.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 181, 182, 183, 184, 185, 186,187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, and200.

In one or more additional embodiments, provided is a compound selectedfrom the group consisting of Compounds 201, 202, 203, 204, 205, 206,207, 208, and 209.

In one or more embodiments, a composition is provided, the compositioncomprising a compound as provided herein and optionally, apharmaceutically acceptable excipient.

In some particular embodiments, a composition is provided, thecomposition comprising a compound encompassed by Formula A or Formula B,or by Formula I or Formula III, and optionally, a pharmaceuticallyacceptable excipient.

In one or more particular embodiments, provided is a compositioncomprising a compound selected from the group consisting of compounds1-209, and a pharmaceutically acceptable excipient.

In one or more embodiments, a composition is provided, the compositioncomprising a compound having the formula

and optionally, a pharmaceutically acceptable excipient.

In one or more embodiments, a dosage form is provided, the dosage formcomprising a compound encompassed by Formula A or Formula B, or byFormula I or Formula III, wherein the compound is present in the dosageform. In some embodiments, the dosage form comprises a compound selectedfrom the group consisting of compounds 1-209.

In some further embodiments, the dosage form is an oral dosage form.

In one or more embodiments, a dosage form is provided, the dosage formcomprising a compound having the formula

wherein the compound is present in a dosage form.

In one or more embodiments, a method is provided, the method comprisingadministering a compound encompassed by Formula A or Formula B, or byFormula I or Formula III to a mammal in need thereof. In someembodiments, the method comprises administering a compound selected fromthe group consisting of compounds 1-209.

In some embodiments, provided is a method for treating neuropathic painby administering a compound encompassed by Formula A or Formula B, or byFormula I or Formula III to a mammal in need thereof. In someembodiments, the method comprises administering a compound selected fromthe group consisting of compounds 1-209 for treating neuropathic pain.

In one or more embodiments, a method is provided, the method comprisingadministering a compound having the formula

to a mammal in need thereof.

Additional embodiments of the compounds, compositions, methods, and thelike will be apparent from the following description, examples, andclaims. As can be appreciated from the foregoing and followingdescription, each and every feature described herein, and each and everycombination of two or more of such features, is included within thescope of the present disclosure provided that the features included insuch a combination are not mutually inconsistent. In addition, anyfeature or combination of features may be specifically excluded from anyembodiment of the present invention. Additional aspects and advantagesof the present invention are set forth in the following description andclaims.

DETAILED DESCRIPTION

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

The term “reactive” or “activated” refers to a functional group thatreacts readily or at a practical rate under conventional conditions oforganic synthesis. This is in contrast to those groups that either donot react or require strong catalysts or impractical reaction conditionsin order to react (i.e., a “nonreactive” or “inert” group).

“Not readily reactive,” with reference to a functional group present ona molecule in a reaction mixture, indicates that the group remainslargely intact under conditions that are effective to produce a desiredreaction in the reaction mixture.

A “protecting group” is a moiety that prevents or blocks reaction of aparticular chemically reactive functional group in a molecule undercertain reaction conditions. The protecting group may vary dependingupon the type of chemically reactive group being protected as well asthe reaction conditions to be employed and the presence of additionalreactive or protecting groups in the molecule. Functional groups whichmay be protected include, by way of example, carboxylic acid groups,amino groups, hydroxyl groups, thiol groups, carbonyl groups and thelike. Representative protecting groups for carboxylic acids includeesters (such as a p-methoxybenzyl ester), amides and hydrazides; foramino groups, carbamates (such as tert-butoxycarbonyl) and amides; forhydroxyl groups, ethers and esters; for thiol groups, thioethers andthioesters; for carbonyl groups, acetals and ketals; and the like. Suchprotecting groups are well-known to those skilled in the art and aredescribed, for example, in T. W. Greefie and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

The term “heteroatom” refers to an atom of any element other than carbonor hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen,phosphorus, sulfur and selenium. Preferred heteroatoms are nitrogen andoxygen.

The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups and branched-chain alkyl groups. In certainembodiments, a straight chain or branched chain alkyl has about 30 orfewer carbon atoms in its backbone (e.g., C₁-C₃₀ for straight chain,C₃-C₃₀ for branched chain), and preferably, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and preferably, have 5, 6 or 7 carbons in the ring structure.Alkyl and cycloalkyl groups, unless otherwise specified, may optionallybe substituted with suitable substituents. The number of substituents istypically limited by the number of available valences on the alkylgroup; thus an alkyl group may be substituted by replacement of one ormore of the hydrogen atoms that would be present on the unsubstitutedgroup.

Suitable substituents for alkyl groups include but are not limited to,for example, halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′₂, SR′, SO₂R′,SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′, CONR′₂,OOCR′, COR′, and NO₂, wherein each R′ is independently H, C₁-C₆ alkyl,C₂-C₆ heteroalkyl, C₁-C₆ acyl, C₂-C₆ heteroacyl, C₆-C₁₀ aryl, C₅-C₁₀heteroaryl, C₇-C₁₂ arylalkyl, or C₆-C₁₂ heteroarylalkyl, each of whichis optionally substituted with one or more groups selected from halo,C₁-C₄ alkyl, C₁-C₄ heteroalkyl, C₁-C₆ acyl, C₁-C₆ heteroacyl, hydroxy,amino, and ═O; and wherein two R′ on the same substituent or on adjacentatoms can be linked to form a 3-7 membered ring optionally containing upto three heteroatoms selected from N, O and S;

Unless the number of carbons is otherwise specified, “lower alkyl”refers to an alkyl group, as defined above, having from one to about sixcarbons in its backbone structure.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzene rings, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl”, “heteroaryl”, or “heterocyclic group” refer to3- to about 10-membered ring structures, alternatively 3- to about7-membered rings, whose ring structures typically include one to fourheteroatoms. Heterocycles may also be bi-cycles or tri-cycles.Heterocyclyl groups include, for example, thiophene, thianthrene, furan,pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole,imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane,thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactamssuch as azetidinones and pyrrolidinones, sultams, sultones, and thelike. The heterocyclic ring may be substituted at one or more positionswith such substituents as described above, as for example, halogen,alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike.

The term “subject” as used herein, refers to an animal, typically amammal or a human, that is the generally the object of treatment,observation, and/or experiment. When the term is used in conjunctionwith administration of a compound as provided herein, then the subjecthas been the object of treatment, observation, and/or administration ofthe compound or drug. The phrase “therapeutically-effective amount” asused herein means that amount of a compound, material, or compositioncomprising a compound as provided herein which is effective forproducing a desired therapeutic effect in at least a sub-population ofcells in an animal at a reasonable benefit/risk ratio applicable to anymedical treatment.

The phrases “parenteral administration” and “administered parenterally”as used herein refer to modes of administration other than enteral andtopical administration, usually by injection, and include, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

A functional group in “protected form” refers to a functional groupbearing a protecting group. As used herein, the term “functional group”or any synonym thereof encompasses protected forms thereof.

Certain compounds of may exist in particular geometric or stereoisomericforms. The present invention contemplates all such compounds, includingwhere applicable, cis- and trans-isomers, R- and S-enantiomers,diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, andother mixtures thereof, as falling within the scope of the invention

As set forth above, the present compounds contain a basic aminofunctional group and are therefore capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptableacids. The term “pharmaceutically-acceptable salts” in this respect,refers to the relatively non-toxic, inorganic and organic acid additionsalts of compounds of the present invention. These salts can be preparedin situ in the administration vehicle or the dosage form manufacturingprocess, or by separately reacting a compound as provided herein in itsfree base form with a suitable organic or inorganic acid, and isolatingthe salt thus formed. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate,valerate, oleate, palmitate, stearate, laurate, benzoate, lactate,phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate,napthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonatesalts and the like. (See, for example, Berge et al. (1977)“Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). Thus, salts asdescribed may be derived from inorganic acids such as hydrochloride,hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; orprepared from organic acids such as acetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic,sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,ethane disulfonic, oxalic, isothionic, and the like.

In some cases, the phenyltriazine compounds provided herein may containone or more acidic functional groups and, thus, are capable of formingpharmaceutically-acceptable salts with pharmaceutically-acceptablebases. The term “pharmaceutically-acceptable salts” in these instancesrefers to the relatively non-toxic, inorganic and organic base additionsalts of compounds of the present invention. These salts can likewise beprepared in situ in the administration vehicle or the dosage formmanufacturing process, or by separately reacting the compound with theacidic group in its free acid form with a suitable base, such as thehydroxide, carbonate or bicarbonate of a pharmaceutically-acceptablemetal cation, with ammonia, or with a pharmaceutically-acceptableorganic primary, secondary or tertiary amine. Representative alkali oralkaline earth salts include the lithium, sodium, potassium, calcium,magnesium, and aluminum salts and the like. Representative organicamines useful for the formation of base addition salts includeethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine,piperazine and the like. (See, for example, Berge et al., supra).

“Substantially” or “essentially” means nearly totally or completely, forinstance, 95% or greater, more preferably 97% or greater, still morepreferably 98% or greater, even more preferably 99% or greater, yetstill more preferably 99.9% or greater, with 99.99% or greater beingmost preferred of some given quantity.

A “biological membrane” is any membrane made of cells or tissues thatserves as a barrier to at least some foreign entities or otherwiseundesirable materials. As used herein a “biological membrane” includesthose membranes that are associated with physiological protectivebarriers including, for example: the blood-brain barrier (BBB); theblood-cerebrospinal fluid barrier; the blood-placental barrier; theblood-milk barrier; the blood-testes barrier; and mucosal barriersincluding the vaginal mucosa, urethral mucosa, anal mucosa, buccalmucosa, sublingual mucosa, and rectal mucosa. Unless the context clearlydictates otherwise, the term “biological membrane” does not includethose membranes associated with the middle gastro-intestinal tract(e.g., stomach and small intestines).

“biological membrane crossing rate,” provides a measure of a compound'sability to cross a biological membrane, such as the blood-brain barrier(“BBB”). A variety of methods may be used to assess transport of amolecule across any given biological membrane. Methods to assess thebiological membrane crossing rate associated with any given biologicalbarrier (e.g., the blood-cerebrospinal fluid barrier, theblood-placental barrier, the blood-milk barrier, the intestinal barrier,and so forth), are known, described herein and/or in the relevantliterature, and/or may be determined by one of ordinary skill in theart.

A “reduced rate of metabolism” refers to a measurable reduction in therate of metabolism of a water-soluble oligomer-small molecule drugconjugate as compared to the rate of metabolism of the small moleculedrug not attached to the water-soluble oligomer (i.e., the smallmolecule drug itself) or a reference standard material. In the specialcase of “reduced first pass rate of metabolism,” the same “reduced rateof metabolism” is required except that the small molecule drug (orreference standard material) and the corresponding conjugate areadministered orally. Orally administered drugs are absorbed from thegastro-intestinal tract into the portal circulation and may pass throughthe liver prior to reaching the systemic circulation. Because the liveris the primary site of drug metabolism or biotransformation, asubstantial amount of drug may be metabolized before it ever reaches thesystemic circulation. The degree of first pass metabolism, and thus, anyreduction thereof, may be measured by a number of different approaches.For instance, animal blood samples may be collected at timed intervalsand the plasma or serum analyzed by liquid chromatography/massspectrometry for metabolite levels. Other techniques for measuring a“reduced rate of metabolism” associated with the first pass, metabolismand other metabolic processes are known, described herein and/or in therelevant literature, and/or may be determined by one of ordinary skillin the art. Preferably, a compound of the invention may provide areduced rate of metabolism [relative to a compound lacking anywater-soluble, non-peptidic oligomer(s)] satisfying at least one of thefollowing values: at least about 30%; at least about 40%; at least about50%; at least about 60%; at least about 70%; at least about 80%; and atleast about 90%. A compound (such as a small molecule drug or conjugatethereof) that is “orally bioavailable” is one that preferably possessesa bioavailability when administered orally of greater than 25%, andpreferably greater than 70%, where a compound's bioavailability is thefraction of administered drug that reaches the systemic circulation inunmetabolized form.

“Pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” refers to component that may be included in the compositions ofthe invention causes no significant adverse toxicological effects to apatient.

“Pharmacologically effective amount,” “physiologically effectiveamount,” and “therapeutically effective amount” are used interchangeablyherein to mean the amount of the compound of the invention present in acomposition that is needed to provide a desired level of the compound(or desired metabolite thereof) the bloodstream or in the target tissue.The precise amount may depend upon numerous factors, e.g., theparticular active agent, the components and physical characteristics ofthe composition, intended patient population, patient considerations,and may readily be determined by one skilled in the art, based upon theinformation provided herein and available in the relevant literature.

A basic reactant or an acidic reactant described herein include neutral,charged, and any corresponding salt forms thereof.

The term “patient,” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of acompound of the invention described herein, and includes both humans andanimals.

“Optional” or “optionally” means that the subsequently describedcircumstance may but need not necessarily occur, so that the descriptionincludes instances where the circumstance occurs and instances where itdoes not.

As indicated above, the present disclosure is directed to (among otherthings) derivatives of 6-(2,3-dichlorophenyl)-1,2,4-triazine-5 aminehaving a substituent at the 3-position of the triazine ring. Thecompounds provided herein each possess an N-bonded substituent at the3-position of the triazine ring and an amino (—NH₂) group at the5-position of the triazine ring, based upon the numbering schemeprovided herein. The N-bonded substituent is an amino nitrogencovalently attached to the 3-carbon of the triazine ring, where theamino nitrogen may be comprised within a substituted acyclic aminomoiety, or may form part of a substituted or unsubstitutednitrogen-containing heterocycle. Illustrative heterocycles include asubstituted or unsubstituted piperazine moiety, a substituted orunsubstituted piperidine, a substituted or an unsubstituted pyrrolidinemoiety, a substituted or an unsubstituted azetidine, or a substituted oran unsubstituted diazetidine, where any of the foregoingnitrogen-containing heterocycles may also form part of a bi- or atricylic ring structure (see for example, compounds 130, 131 (fused ringsystems), and compounds 141 and 161).

Generally, the compounds provided herein possess the following generalstructure:

The amino linked moiety as shown in Formula A is attached to the3-carbon of the triazine ring by an amino-linkage, where the amino groupmay be a primary amino group (—NH₂), or may be a secondary or a tertiaryamino group (comprising one or no hydrogens, respectively). The aminogroup is generally but not necessarily a substituted amino group, i.e.,having one or no hydrogens. The amino group may, for example, besubstituted with an alkyl chain(s) that is linear or branched, and/ormay comprise an oligomeric ethylene oxide chain, both of which may befurther substituted. In one or more embodiments, substituents includeone or more functional groups selected from, for example, oxygen(ether), amino, hydroxyl, carboxyl, carbonyl, sulfonyl, aldehyde,alkylsulfone, tetrazole, carbonyl, oxetane, carbonate, alkyl ester,sulfoxide, halo, amido, sulfonamide, cycloalkyl, heterocyclyl, —CF₃,—CF₂H, CFH₂, and the like.

In some embodiments, the amino group linked to the 3-carbon of thetriazine ring may also be comprised within a ring structure. The aminogroup may, for example, be comprised within a substituted orunsubstituted piperazine moiety, or within a substituted orunsubstituted pyrrolidine moiety, or within a substituted orunsubstituted piperidine, or within a substituted or unsubstitutedazetidine, or within a substituted or unsubstituted diazetidine, and thelike, or may be comprised within a bicyclic ring comprising one of theforegoing heterocycles, such as a hexahydropyrazino-oxazin-one, orhexahydropyrazino-oxazine, diazaspiro-octane, diazaspiro-nonane, and thelike. Substituted ring structures include rings as described abovesubstituted with an alkyl chain that is linear or branched, and/or withan oligomeric ethylene oxide chain (that may comprise a substituent onan alkyl chain) both of which may be further substituted. In one or moreembodiments, substituents include one or more functional groups selectedfrom, for example, oxygen (ether), amino, hydroxyl, carboxyl, carbonyl,sulfonyl, aldehyde, alkylsulfone, tetrazole, carbonyl, oxetane,carbonate, alkyl ester, sulfoxide, halo, amido, sulfonamide, cycloalkyl,heterocyclyl, —CF₃, —CF₂H, CFH₂, and the like.

In some embodiments, the dichlorophenyl ring of the compounds maypossess an additional substituent at any one of positions 4, 5 or 6,where the substituent is selected from halo, hydroxyl, and oligomericethylene oxide (—OCH₂CH₂)_(n)OR, where n is in a range from 1-7 and R isselected from H, -lower alkyl, preferably methyl, and fluoro-substitutedmethyl (e.g., —CF₃, —CHF₂, —CH₂F). Exemplary compounds having anadditional substituent on the phenyl ring include compounds 104, 106,109, 110, 119, 123 (5-fluoro substituted compounds), compound 164(4-hydroxy substituted), and compound 112 (having a oligomeric ethyleneoxide group at the 4-ring position, —(OCH₂CH₂)₃OCH₃.

In some embodiments, derivatives of6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine having the followingstructure are provided:

where M is a substituted amino moiety —NR₆R₇, wherein: (i) R₆ and R₇ areeach independently selected from the group consisting of H, lower alkyl,—(CH₂CH₂O)_(m)R₈, —CH₂CH₂-(3-7 membered heterocycloalkyl),—C(O)—CH₂(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀,—CR₁₁R₁₂CH₂OH, —CR₁₁R₁₂CH₂O(CH₂CH₂O)₁₋₇R₁₀, —CH—[CH₂OH]₂; —CCH₃(CH₂OH)₂,—CCH₃(CH₂OH)CH₂O(CH₂CH₂O)₁₋₇R₁₀, alkylamino, hydroxyalkylamino,—CH₂CH₂NCH₃C(O)CH₂(OCH₂CH₂)₁₋₇R₁₀, —CH₂CH₂NCH₃C(O)CH₂OCH₂C(O)NH₂,—CH₂CH₂NCH₃(CH₂CH₂O)₁₋₇R₁₀, —CR₁₁R₁₂CH(O), —CR₁₁R₁₂(CH₂)₁ or₂SO₂—CH₂CH₂O)₁₋₇R₁₀, —CCH₃(CH₂OCH₂CH₂OCH₃)₂, —OCH₂CR₉HCH₂R₁₀

—CH₂CR₉HCH₂NHC(O)CH₂O(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂NHC(O)CH₂OCH₂C(O)NH₂,and —(OCH₂CH₂)_(m)OR₁₀, with the proviso that R₆ and R₇ are not both H,or,

(ii) wherein R₆ and R₇ taken together with N form a heterocycloalkylring selected from piperazine, piperidine, and azetidine, which mayoptionally form part of a bicyclic ring structure, where theheterocycloalkyl ring or bicyclic ring is either unsubstituted or issubstituted with a group selected from lower alkyl, —(CH₂CH₂O)_(m)R₈,—C(O)—CH₂(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂O(CH₂CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀,—CH₂CH₂SO₂CH₃, —NR₉(CH₂CH₂O)_(m)R₁₀, tetra-hydro-2H-pyranyl,piperidinyl, —CH₂OH, —CH₂R₁₀, amino, —CHCH₃CH₂OH, hydroxyl,—CR₁₁R₁₂CH₂OH, —C(O)OCH₃, —CF₃, —CH₂C(OH)CF₃, —CH₂OCH₂—C₆H₅F, and—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₃, with variables having thevalues as set forth below:

m is in a range from 0-29,

R₈ is selected from H, C1-C6 alkyl, fluoro-substituted methyl (e.g.,—CF₃, —CF₂H, or —CFH₂), —CH₂COOR₀, —CH₂COCH₃, 3-7 memberedheterocycloalkyl, 3-7 membered heteroaryl, heteroarylalkyl, —C(O)OCH₃,C1-C6 alkyl substituted with one or more of hydroxyl, amino, alkylamino,amido, alkylamide, amidoalkylamine, acylamino, carboxyalkylamino,sulfonamide, sulfone, alkylsulfone, alkoxyalkyl sulfone,alkyloxyalklsulfoxide, 3-7 membered heterocycloalkyl, 5-6 memberedheteroaryl, carboxyl, —NHCH₂CH₂OCH₃, —NHCHR₉COOR₁₁; and—CH—[CH₂O—(CH₂CH₂O)₂₋₈CH₃]₂;

R₉ is H, lower alkyl, hydroxyl,

R₁₀ is selected from H, lower alkyl and fluoro-substituted methyl,

R₁₁ and R₁₂ are each independently selected from H and lower alkyl,

R₁₃ is cyclopropyl or cyclobutyl, and

W is an optional substituent (where the subscript zero indicates itsabsence and the subscript 1 indicates its presence) selected from halo,hydroxyl, and oligomeric ethylene oxide (—OCH₂CH₂)_(n)OR, where n rangesfrom 1-7 and R is selected from H, -lower alkyl, preferably methyl, andfluoro-substituted methyl (e.g., —CF₃, —CHF₂, —CH₂F).

In some embodiments, when R₆ is H and W is absent, and R₇ does not equal—(CH₂CH₂O)₂₋₁₁CH₃.

In one or more embodiments, R₆ is H.

In some embodiments, R₆ and R₇ are each independently selected from thegroup consisting of H, lower alkyl, —(CH₂CH₂O)_(m)R₈, —CH₂CH₂-(3-7membered heterocycloalkyl), —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CR₁₁R₁₂CH₂OH,—CR₁₁R₁₂CH₂O(CH₂CH₂O)₁₋₇R₁₀, —CH—[CH₂OH]₂; —CCH₃(CH₂OH)₂,—CCH₃(CH₂OH)CH₂O(CH₂CH₂O)₁₋₇R₁₀, alkylamino, hydroxyalkylamino,—CH₂CH₂NCH₃C(O)CH₂(OCH₂CH₂)₁₋₇R₁₀, —CH₂CH₂NCH₃C(O)CH₂OCH₂C(O)NH₂,—CH₂CH₂NCH₃(CH₂CH₂O)₁₋₇R₁₀, —CR₁₁R₁₂CH(O), —CR₁₁R₁₂(CH₂)₁ or₂SO₂—CH₂CH₂O)₁₋₇R₁₀, —CCH₃(CH₂OCH₂CH₂OCH₃)₂, —OCH₂CR₉HCH₂OR₁₀—CH₂CR₉HCH₂NHC(O)CH₂O(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂NHC(O)CH₂OCH₂C(O)NH₂,and —(OCH₂CH₂)_(m)OR₁₀, where variables possess the values providedabove, and with the proviso that R₆ and R₇ are not both H.

In yet some further embodiments, R₆ is H and R₇ is selected from thegroup consisting of H, lower alkyl, —(CH₂CH₂O)_(m)R₈, —CH₂CH₂-(3-7membered heterocycloalkyl), —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂)_(m)(CH₂)_(0,1)R₁₀, —CR₁₁R₁₂CH₂OH,—CR₁₁R₁₂CH₂O(CH₂CH₂O)₁₋₇R₁₀, —CH—[CH₂OH]₂; —CCH₃(CH₂OH)₂,—CCH₃(CH₂OH)CH₂O(CH₂CH₂O)₁₋₇R₁₀, alkylamino, hydroxyalkylamino,—CH₂CH₂NCH₃C(O)CH₂(CH₂CH₂)₁₋₇R₁₀, —CH₂CH₂NCH₃C(O)CH₂OCH₂C(O)NH₂,—CH₂CH₂NCH₃(CH₂CH₂O)₁₋₇R₁₀, —CR₁₁R₁₂CH(O), —CR₁₁R₁₂(CH₂)₁ or₂SO₂—CH₂CH₂O)₁₋₇R₁₀, —CCH₃(CH₂OCH₂CH₂OCH₃)₂, —OCH₂CR₉HCH₂OR₁₀—CH₂CR₉HCH₂NHC(O)CH₂O(CH₂CH₂O)_(m)R₁₀, —CH₂CR₉HCH₂NHC(O)CH₂OCH₂C(O)NH₂,and —(OCH₂CH₂)_(m)OR₁₀, where variables possess the values providedabove.

In some preferred embodiments, m is selected from 0, 1, 2, 3, 4, 5, 6,and 7.

In some additional embodiments, R₆ and R₇ taken together with N form aheterocycloalkyl ring selected from piperazine, piperidine, andazetidine, which may optionally form part of a bicyclic ring structure,where the heterocycloalkyl ring or bicyclic ring is either unsubstitutedor is substituted with a group selected from lower alkyl,—(CH₂CH₂O)_(m)R₈, —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CH₂CH₂SO₂CH₃,—NR₉(CH₂CH₂O)_(m)R₁₀, tetra-hydro-2H-pyranyl, piperidinyl, —CH₂OH,—CH₂R₁₀, amino, —CHCH₃CH₂OH, hydroxyl, —CR₁₁R₁₂CH₂OH, —C(O)OCH₃, —CF₃,—CH₂C(OH)CF₃, —CH₂OCH₂—C₆H₅F, and—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₃, where variables such as m, R₈,R₉, R₁₀, R₁₁, R₁₂, and R₁₃ possess the values provided above.

In one or more embodiments, R₆ is H and R₇ is —(CH₂CH₂O)_(m)R₈, where mis selected from 1, 2, 3, 4, 5, 6, and 7, and R₈ is selected from H,methyl, isopropyl, fluoro-substituted methyl, carboxyl, and 3-7 memberedheterocycloalkyl. In one or more related embodiments, the 3-7 memberedring heterocycloalkyl is selected from tetrazole, oxetane andpiperazine.

In some embodiments, R₆ and R₇ taken together with N form aheterocycloalkyl ring selected from piperazine, piperidine, andazetidine. In some particular embodiments, R₆ and R₇ taken together withN form an unsubstituted or a substituted piperazine. Exemplarysubstituted piperazines include those having a N-substituent selectedfrom —(CH₂CH₂O)₁₋₇C1-C6 alkyl or fluoro-substituted methyl,—(CH₂CH₂O)₁₋₇CH₂CH₂NHSO₂CH₃,

—C(O)CH₂O(CH₂CH₂O)₁₋₇CH₃, —CH₂CHOHCH₂OCF₃,—CH₂CHOHCH₂OCH₂CF₃—CH₂CHOHCH₂OCH₃, —CH₂OH, —(CH₂CH₂O)₂OH, —CH₂CH₂SO₂CH₃,—CH₂CH₂OCH₂COOH, —CH₂CH₂OCH₂COOC(CH₃)₃, —CH₂CH(OH)CH₂OH,—C(CH₃)₂CH₂OCH₂CH₂OH,

—CH₂CF₃, —CHCH₃CH₂OH, —C(CH₃)₂CH₂OH, and —CH₂CH(OH)CH₂Cl. Exemplarycompounds wherein R₆ and R₇ taken together with N form an unsubstitutedor a substituted piperazine include compounds 92, 103, 104, 105, 106,113, 120, 121, 122, 123, 96, 97, 87, 89, 88, 90, 94, 207, 98, 13, 136,137, 208, 124, 27, 200, 201, 202, 203, 204, 138, 139, 140, 55, 73, 78,80, and 83.

In some additional embodiments, R₆ and R₇ taken together with N form aring selected from substituted pyrrolidine, substituted piperazine, andsubstituted piperazine forming part of a bicyclic ring system, e.g.,tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (as in compound 128),tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (as in compound 127), andhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (as in compound 130), andazetidine.

In some preferred embodiments, the compound is selected from the groupconsisting of: (2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97),(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol2HCl (Compound 95),(R)-1-((1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75), 3-N-(3-hydroxyazetin-1-yl) lamotrigine (Compound 129),1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27),(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)lamotrigine di HCl (Compound 120), and(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130).

In some further embodiments, compounds as provided herein contain anamino nitrogen covalently attached to the 3-carbon of the triazine ring,where the amino nitrogen may be comprised within a substituted acyclicamino moiety, within a substituted piperazine moiety, or within asubstituted pyrrolidine moiety. Compounds falling within the particularmolecular scaffolds described herein possess unique properties, to bedescribed in greater detail herein.

In one or more embodiments, a derivative of6-(2,3-dichlorophenyl)-1,2,4-triazine-5 amine having a substituent atthe 3-position of the triazine ring may fall within the followinggeneralized structure:

In the foregoing structure, the overall boxed moiety represents asubstituted amino moiety, wherein the moiety comprises an amino nitrogencovalently attached to the 3-carbon of the triazine ring, where theamino nitrogen may be comprised within a substituted acyclic aminomoiety, within a substituted piperazine moiety, or within a substitutedpyrrolidine moiety. Thus, one feature of the instant compounds is thepresence of an amino nitrogen covalently attached to the 3-ring positionof the triazine ring.

Representative compounds possess the following features. For example inone or more embodiments, A is one of

Turning now to variable G, exemplary G groups are oxygen, methylene(˜CH₂˜), substituted methylene where the methylene group may besubstituted with alkyl groups such as lower alkyl (methyl, ethyl,propyl, butyl, pentyl, and hexyl, or branched forms thereof) orsubstituted lower alkyl, where the alkyl substituent may comprise ahydroxyl, or an ethylene oxide segment comprising from 1-5 repeat units,and having a terminal hydroxy or methoxy group, or lower alkylene orsubstituted lower alkylene as described above. Illustrative G groupsinclude the following: ˜O˜, ˜CH₂˜,

For example, when G is

where G is selected from the following:

Turning now to the substituent adjacent to the G in Formula (I),“˜CH(O)_(p)H˜,” p is 0 or 1 (where a value of 0 indicates the absence ofoxygen and a value of 1 indicates its presence), such that this moietyis either methylene or ˜CH(OH)˜.

Variable J in reference to Formula (I) is typically a substituted alkylor substituted araalkyl, optionally comprising an ether oxygen or anether, where each J generally includes one or more oxygen atoms.Illustrative J groups are selected from ˜CH(OH)CH₂OH, ˜CH(OH)CH₂OCH₃,˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂, ˜OCH(CH₂OH)₂,˜(OCH₂CH₂)₀₋₂₉OR¹, where R¹ equals methyl or fluoro-substituted methyl(e.g., —CF₃, —CF₂H, or —CFH₂), ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃.

In yet one or more further embodiments, when J is ˜(OCH₂CH₂)₀₋₂₉OR¹, Jis selected from ˜(OCH₂CH₂)OR¹, ˜(OCH₂CH₂)₂OR¹, ˜(OCH₂CH₂)₃OR¹,˜(OCH₂CH₂)₄OR¹, ˜(OCH₂CH₂)₅OR¹, ˜(OCH₂CH₂)₆OR₁, ˜(OCH₂CH₂)₆OR¹,˜(OCH₂CH₂)₈OR¹, ˜(OCH₂CH₂)₉OR¹, and ˜(OCH₂CH₂)₁₀OR¹.

In yet one or more additional embodiments, when J is ˜(OCH₂CH₂)₀₋₂₉OR¹,J is further selected from ˜OR¹ and ˜(OCH₂CH₂)₁₋₁₀OR¹.

In reference to the variables provided above for A, G, p, and J,compounds in accordance with the disclosure are meant to encompass eachand every combination of illustrative A, G, p, and J moieties asprovided above.

A representative structure is provided below as Formula II, where theamino group substituted at the 3-position of the triazine ring comprisesa trifluoromethoxy terminal group and ethyoxy-subunits (from 1 to 30)within the alkyl chain.

The number of ethoxy subunits is selected from the group consisting of1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, and 30.

In yet one or more embodiments related to the foregoing, n is an integerselected from 1-15 or from 1-10.

Also provided herein is a compound having the formula:

Additional compounds provided herein are those comprising a pyrrolidinesubstituent at the 3-position of the triazine ring. Generally, suchcompounds are described by Formula III,

where R₂ is either H or ˜CH₂C(OH)CH₂OCH₃, and S₁ is an optionalsubstituent selected from ˜OCH₂CH₃ and

Illustrative compounds in accordance with Formula (I) are those in whichA is

G is

p is 0, and J is selected from ˜CH(OH)CH₂OH, ˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH,˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂, ˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹,where R¹ equals methyl or fluoro-substituted methyl (e.g., —CF₃, —CF₂H,or —CFH₂), ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃.

Additional compounds in accordance with Formula (I) are those in which Ais

G is

p is 0, and J is selected from ˜OH, ˜OCH₂CH₂OH, ˜OCF₂H,˜OCH₂C(OH)HCH₂OCH₃ and ˜(OCH₂CH₂)₂OCF₃.

Yet additional compounds in accordance with Formula (I) are those inwhich A is either

G is ˜CH₂˜, p is 0 or 1, and J is selected from ˜CH(OH)CH₂OH,˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂,˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹, where R¹ equals methyl orfluoro-substituted methyl (e.g., —CF₃, —CF₂H, or —CFH₂), ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃.

Yet additional compounds in accordance with Formula (I) are those inwhich A is either

G is ˜CH₂˜, p is 0, and J is selected from ˜OCH(CH₂OH)₂, ˜OCH(CH₂OCH₃)₂,˜OCF₃, ˜(OCH₂CH₂)OCF₃, ˜CH(OH)CH₂OCH₃, ˜CH₂OCH₂CH₃, ˜(OCH₂CH₂)₂OCF₂H.

Additional representative compounds include those in accordance withFormula (I), where A is

G is ˜CH₂˜, p is 1, and J is ˜CH₂OCF₃.

Further compounds are those in which A is

G is

p is 0, and J is selected from the group consisting of ˜CH(OH)CH₂OH,˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂,˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹, where R¹ equals methyl orfluoro-substituted methyl (e.g., —CF₃, —CF₂H, or —CFH₂), ˜CH₂OCH₂CH₃,

and —OCH₂C(OH)HCH₂OCH₃.

Additional exemplary compounds include those in which A is

G is

p is 0, and J is selected from the group consisting of ˜OH,(OCH₂CH₂)OCH₃, and

Exemplary compounds of formula (I) include those in which A is

such as the following:

Additional compounds as provided herein are those wherein, in referenceto Formula (I), A is

Illustrative compounds include the following:

Representative 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine derivativecompounds comprising a substituted pyrrolidine at the 3-position of thetriazine ring include:

Further compounds as described generally above are provided in theaccompanying Examples.

With respect to the blood-brain barrier (“BBB”), this barrier restrictsthe transport of drugs from the blood to the brain. This barrierconsists of a continuous layer of unique endothelial cells joined bytight junctions. The cerebral capillaries, which comprise more than 95%of the total surface area of the BBB, represent the principal route forthe entry of most solutes and drugs into the central nervous system.

For compounds whose degree of blood-brain barrier crossing ability isnot readily known, such ability may be determined using a suitableanimal model such as an in situ rat brain perfusion (“RBP”) model asdescribed herein. Briefly, the RBP technique involves cannulation of thecarotid artery followed by perfusion with a compound solution undercontrolled conditions, followed by a wash out phase to remove compoundremaining in the vascular space. (Such analyses may be conducted, forexample, by contract research organizations such as Absorption Systems,Exton, Pa.). In one example of the RBP model, a cannula is placed in theleft carotid artery and the side branches are tied off. A physiologicbuffer containing the analyte (typically but not necessarily at a 5micromolar concentration level) is perfused at a flow rate of about 10mL/minute in a single pass perfusion experiment.

After 30 seconds, the perfusion is stopped and the brain vascularcontents are washed out with compound-free buffer for an additional 30seconds. The brain tissue is then removed and analyzed for compoundconcentrations via liquid chromatography with tandem mass spectrometrydetection (LC/MS/MS). Alternatively, blood-brain barrier permeabilitycan be estimated based upon a calculation of the compound's molecularpolar surface area (“PSA”), which is defined as the sum of surfacecontributions of polar atoms (usually oxygens, nitrogens and attachedhydrogens) in a molecule. The PSA has been shown to correlate withcompound transport properties such as blood-brain barrier transport.Methods for determining a compound's PSA can be found, e.g., Ertl et al.(2000) J. Med. Chem. 43:3714-3717 and Kelder et al. (1999) Pharm. Res.16:1514-1519.

With respect to the blood-brain barrier, a6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine derivative compound asprovided herein exhibits a blood-brain barrier crossing rate. It ispreferred that such a rate is relatively reduced (e.g., reduced whencompared to the rate of lamotrigine). Exemplary reductions inblood-brain barrier crossing rates for the compounds described hereininclude reductions of: at least about 5%; at least about 10%; at leastabout 25%; at least about 30%; at least about 40%; at least about 50%;at least about 60%; at least about 70%; at least about 80%; or at leastabout 90%, when compared to the blood-brain barrier crossing rate oflamotrigine.

Assays for determining whether a given phenyltriazine compound such asthose provided herein has anticonvulsant activity (e.g., as evidencedthrough a maximal electroshock test) are known. One such assay isdescribed in L. A. Woodbury and V. D. Davenport (1952) Design and Use ofa New Electroshock Seizure Apparatus, and Analysis of Factors AlteringSeizure Threshold and Pattern Arch Int Pharmacodyn Ther 92:97-104.

The compounds described herein can be present in a racemic mixture andin an optically active form, for example, a single optically activeenantiomer, or any combination or ratio of enantiomers (e.g., scalemicand racemic mixtures). In addition, the6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine derivative compound maypossess one or more geometric isomers. With respect to geometricisomers, a composition can comprise a single geometric isomer or amixture of two or more geometric isomers. A small molecule drug for useas set forth herein can be in its customary active form, or may possesssome degree of modification.

Animal models (rodents and dogs) can be used to study oral drugtransport. In addition, non-in vivo methods include rodent everted gutexcised tissue and Caco-2 cell monolayer tissue-culture models. Thesemodels are useful in predicting oral drug bioavailability.

To determine whether a 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-aminederivative compound has potential pharmacological activity, the compoundmay be evaluated using, for example, the various approaches as set forthin the Examples section. For example, in vitro binding studies toreceptors using various cell lines expressing these receptors that havebecome routine in pharmaceutical industry, and can be used to determinewhether a given compound has potential pharmacological activity.

Turning now to the examples, Example 154 describes the efficacy ofcertain exemplary compounds as sodium channel blockers. Preferredcompounds, in terms of sodium channel blocking activity, are thosecompounds described in Table 2 that demonstrate an IC₅₀ tonic statevalue as indicated in the table of greater than (>) a value that is 200μM. In one or more additional embodiments, preferred are compounds thatdemonstrate an IC₅₀ inactivated state value as provided in the table ofless than (<) a value that is 50 μM. Such compounds are described in theexample.

In terms of pharmacokinetics, Example 155 describes certainpharmacokinetic properties of illustrative compounds as provided herein.As provided in Example 155, clearance parameters (CL), bioavailabilities(F) and half-lives were calculated. Particularly preferred compounds arethose described in Table 3, having a single asterisk. Of the compoundsevaluated, these compounds exhibited the most favorablepharmacokinetics. Each of the compounds possesses a substituted tertiaryamino group attached at the 3-position of the triazine ring, where thetertiary amino group forms part of a ring system. The substituted ringsystems include substituted pyrrolidine, substituted piperazine, andsubstituted piperazine forming part of a bicyclic ring system, e.g.,tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (compound 128),tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (compound 127), andhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (compound 130), andazetidine.

Specifically, compounds demonstrating the most favorablepharmacokinetics include: (2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97),(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol.2HCl(Compound 95),(R)-1-((1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75), 3-N-(3-hydroxyazetin-1-yl) lamotrigine (Compound 129),1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27),(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)lamotrigine di HCl (Compound 120), and(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130).

Still, in reference to Example 155, compounds that exhibited the bestexposure after oral dosing are indicated in the table by (**). Thesecompounds are, in some embodiments, preferred.

Additionally, provided in Example 156 is data related to potencies ofcertain illustrative compounds as provided herein in treating chronic oracute pain. In one or more embodiments, the compounds are effective intreating neuropathic pain. Animal models used to assess the ability ofthe compounds for treating pain included mechanical allodynia, AFP, RR,and hyperalgesia models. Some preferred compounds, based upon potencyindications, include compounds 167(6-(2,3-dichlorophenyl)-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine)and 98((S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol).

The compounds of the invention may be administered per se or in the formof a pharmaceutically acceptable salt, and any reference to thecompounds of the invention herein is intended to includepharmaceutically acceptable salts. If used, a salt of a compound asdescribed herein should be both pharmacologically and pharmaceuticallyacceptable, but non-pharmaceutically acceptable salts may convenientlybe used to prepare the free active compound or pharmaceuticallyacceptable salts thereof and are not excluded from the scope of thisinvention. Such pharmacologically and pharmaceutically acceptable saltscan be prepared by reaction of the compound with an organic or inorganicacid, using standard methods detailed in the literature. Examples ofuseful salts include, but are not limited to, those prepared from thefollowing acids: hydrochloric, hydrobromic, sulfuric, nitric,phosphoric, maleic, acetic, salicyclic, p-toluenesulfonic, tartaric,citric, methanesulfonic, formic, malonic, succinic,naphthalene-2-sulphonic and benzenesulphonic, and the like. Also,pharmaceutically acceptable salts can be prepared as alkaline metal oralkaline earth salts, such as sodium, potassium, or calcium salts of acarboxylic acid group.

Also provided are pharmaceutical preparations comprising a6-(2,3-dichlorophenyl)-1,2,4-triazin-5-amine derivative compound asdescribed herein in combination with a pharmaceutical excipient.Generally, the compound itself will be in a solid form (e.g., aprecipitate, in crystalline form, optionally in the form of a hydrate orsolvate), which can be combined with a suitable pharmaceutical excipientthat may be in either solid or liquid form.

Exemplary excipients include, without limitation, those selected fromthe group consisting of carbohydrates, inorganic salts, antimicrobialagents, antioxidants, surfactants, buffers, acids, bases, andcombinations thereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol,aldonic acid, an esterified sugar, and/or a sugar polymer may be presentas an excipient. Specific carbohydrate excipients include, for example:monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, maltitol, lactitol, xylitol, sorbitol,myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such ascitric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof.

The preparation may also include an antimicrobial agent for preventingor deterring microbial growth. Nonlimiting examples of antimicrobialagents suitable for the present invention include benzalkonium chloride,benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate,thimersol, and combinations thereof.

An antioxidant can be present in the preparation as well. Antioxidantsare used to prevent oxidation, thereby preventing the deterioration ofthe conjugate or other components of the preparation. Suitableantioxidants for use in the present invention include, for example,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorous acid, monothioglycerol, propyl gallate, sodiumbisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, andcombinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude: polysorbates, such as “Tween 20” and “Tween 80,” and pluronicssuch as F68 and F88 (both of which are available from BASF, Mount Olive,N.J.); sorbitan esters; lipids, such as phospholipids such as lecithinand other phosphatidylcholines, phosphatidylethanolamines, fatty acidsand fatty esters; steroids, such as cholesterol; and chelating agents,such as EDTA, zinc and other such suitable cations.

Pharmaceutically acceptable acids or bases may be present as anexcipient in the preparation. Nonlimiting examples of acids that can beused include those acids selected from the group consisting ofhydrochloric acid, acetic acid, phosphoric acid, citric acid, malicacid, lactic acid, formic acid, trichloroacetic acid, nitric acid,perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, andcombinations thereof. Examples of suitable bases include, withoutlimitation, bases selected from the group consisting of sodiumhydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide,ammonium acetate, potassium acetate, sodium phosphate, potassiumphosphate, sodium citrate, sodium formate, sodium sulfate, potassiumsulfate, potassium fumerate, and combinations thereof.

The amount of the 6-(2,3-dichlorophenyl)-1,2,4-triazin-5-aminederivative compound will vary depending on a number of factors, but willoptimally be a therapeutically effective dose when the composition isstored in a unit dose container. A therapeutically effective dose can bedetermined experimentally by repeated administration of increasingamounts of the compound in order to determine which amount produces aclinically desired endpoint.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. The optimal amount of any individual excipient isdetermined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thendetermining the range at which optimal performance is attained with nosignificant adverse effects.

Generally, however, excipients will be present in the composition in anamount of about 1% to about 99% by weight, preferably from about 5%-98%by weight, more preferably from about 15-95% by weight of the excipient,with concentrations less than 30% by weight most preferred.

These foregoing pharmaceutical excipients along with other excipientsand general teachings regarding pharmaceutical compositions aredescribed in “Remington: The Science & Practice of Pharmacy”, 19^(th)ed., Williams & Williams, (1995), the “Physician's Desk Reference”,52^(nd) ed., Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H.,Handbook of Pharmaceutical Excipients, 3^(rd) Edition, AmericanPharmaceutical Association, Washington, D.C., 2000.

The pharmaceutical compositions can take any number of forms and theinvention is not limited in this regard. Exemplary preparations are mostpreferably in a form suitable for oral administration such as a tablet,caplet, capsule, gel cap, troche, dispersion, suspension, solution,elixir, syrup, lozenge, transdermal patch, spray, suppository, andpowder.

Oral dosage forms are preferred for those conjugates that are orallyactive, and include tablets, caplets, capsules, gel caps, suspensions,solutions, elixirs, and syrups, and can also comprise a plurality ofgranules, beads, powders or pellets that are optionally encapsulated.Such dosage forms are prepared using conventional methods known to thosein the field of pharmaceutical formulation and described in thepertinent texts.

Tablets and caplets, for example, can be manufactured using standardtablet processing procedures and equipment. Direct compression andgranulation techniques are preferred when preparing tablets or capletscontaining the conjugates described herein. In addition to theconjugate, the tablets and caplets will generally contain inactive,pharmaceutically acceptable carrier materials such as binders,lubricants, disintegrants, fillers, stabilizers, surfactants, coloringagents, flow agents, and the like. Binders are used to impart cohesivequalities to a tablet, and thus ensure that the tablet remains intact.Suitable binder materials include, but are not limited to, starch(including corn starch and pregelatinized starch), gelatin, sugars(including sucrose, glucose, dextrose and lactose), polyethylene glycol,waxes, and natural and synthetic gums, e.g., acacia sodium alginate,polyvinylpyrrolidone, cellulosic polymers (including hydroxypropylcellulose, hydroxypropyl methylcellulose, methyl cellulose,microcrystalline cellulose, ethyl cellulose, hydroxyethylcellulose, andthe like), and Veegum. Lubricants are used to facilitate tabletmanufacture, promoting powder flow and preventing particle capping(i.e., particle breakage) when pressure is relieved. Useful lubricantsare magnesium stearate, calcium stearate, and stearic acid.Disintegrants are used to facilitate disintegration of the tablet, andare generally starches, clays, celluloses, algins, gums, or crosslinkedpolymers. Fillers include, for example, materials such as silicondioxide, titanium dioxide, alumina, talc, kaolin, powdered cellulose,and microcrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Stabilizers, as well known in the art, are used to inhibit orretard drug decomposition reactions that include, by way of example,oxidative reactions.

Capsules are also preferred oral dosage forms, in which case theconjugate-containing composition can be encapsulated in the form of aliquid or gel (e.g., in the case of a gel cap) or solid (includingparticulates such as granules, beads, powders or pellets). Suitablecapsules include hard and soft capsules, and are generally made ofgelatin, starch, or a cellulosic material. Two-piece hard gelatincapsules are preferably sealed, such as with gelatin bands or the like.

Included are parenteral formulations in the substantially dry form (as alyophilizate or precipitate, which can be in the form of a powder orcake), as well as formulations prepared for injection, which are liquidand require the step of reconstituting the dry form of parenteralformulation. Examples of suitable diluents for reconstituting solidcompositions prior to injection include bacteriostatic water forinjection, dextrose 5% in water, phosphate-buffered saline, Ringer'ssolution, saline, sterile water, deionized water, and combinationsthereof.

In some cases, compositions intended for parenteral administration cantake the form of nonaqueous solutions, suspensions, or emulsions,normally being sterile. Examples of nonaqueous solvents or vehicles arepropylene glycol, polyethylene glycol, vegetable oils, such as olive oiland corn oil, gelatin, and injectable organic esters such as ethyloleate.

The parenteral formulations described herein can also contain adjuvantssuch as preserving, wetting, emulsifying, and dispersing agents. Theformulations are rendered sterile by incorporation of a sterilizingagent, filtration through a bacteria-retaining filter, irradiation, orheat.

The compounds of the invention can also be administered through the skinusing conventional transdermal patch or other transdermal deliverysystem, wherein the conjugate is contained within a laminated structurethat serves as a drug delivery device to be affixed to the skin. In sucha structure, the compound is contained in a layer, or “reservoir,”underlying an upper backing layer. The laminated structure can contain asingle reservoir, or it can contain multiple reservoirs.

The compounds of the invention can also be formulated into a suppositoryfor rectal administration. With respect to suppositories, the compoundis mixed with a suppository base material which is (e.g., an excipientthat remains solid at room temperature but softens, melts or dissolvesat body temperature) such as coca butter (theobroma oil), polyethyleneglycols, glycerinated gelatin, fatty acids, and combinations thereof.Suppositories can be prepared by, for example, performing the followingsteps (not necessarily in the order presented): melting the suppositorybase material to form a melt; incorporating the compound (either beforeor after melting of the suppository base material); pouring the meltinto a mold; cooling the melt (e.g., placing the melt-containing mold ina room temperature environment) to thereby form suppositories; andremoving the suppositories from the mold.

In some embodiments of the invention, the compositions comprising thecompounds of the invention may further be incorporated into a suitabledelivery vehicle. Such delivery vehicles may provide controlled and/orcontinuous release of the compounds and may also serve as a targetingmoiety. Non-limiting examples of delivery vehicles include, adjuvants,synthetic adjuvants, microcapsules, microparticles, liposomes, and yeastcell wall particles. Yeast cells walls may be variously processed toselectively remove protein component, glucan, or mannan layers, and arereferred to as whole glucan particles (WGP), yeast beta-glucan mannanparticles (YGMP), yeast glucan particles (YGP), Rhodotorula yeast cellparticles (YCP). Yeast cells such as S. cerevisiae and Rhodotorulaspecies are preferred; however, any yeast cell may be used. These yeastcells exhibit different properties in terms of hydrodynamic volume andalso differ in the target organ where they may release their contents.The methods of manufacture and characterization of these particles aredescribed in U.S. Pat. Nos. 5,741,495, 4,810,646, 4,992,540, 5,028,703,5,607,677, and U.S. Patent Application Publication Nos. 2005/0281781 and2008/0044438.

The invention also provides a method for administering a compound of theinvention as provided herein to a patient suffering from a conditionthat is responsive to treatment with the compound. The method comprisesadministering, generally orally, a therapeutically effective amount ofthe compound (preferably provided as part of a pharmaceuticalpreparation). Other modes of administration are also contemplated, suchas pulmonary, nasal, buccal, rectal, sublingual, transdermal, andparenteral. As used herein, the term “parenteral” includes subcutaneous,intravenous, intra-arterial, intraperitoneal, intracardiac, intrathecal,and intramuscular injection, as well as infusion injections.

The method of administering may be used to treat any condition that canbe remedied or prevented by administration of a particular compound ofthe invention. Those of ordinary skill in the art appreciate whichconditions a specific compound can effectively treat. Exemplaryconditions include conditions requiring anticonvulsant therapy and/orprophylaxis and pain. The actual dose to be administered will varydepend upon the age, weight, and general condition of the subject aswell as the severity of the condition being treated, the judgment of thehealth care professional, and conjugate being administered.Therapeutically effective amounts are known to those skilled in the artand/or are described in the pertinent reference texts and literature.Generally, a therapeutically effective amount will range from about0.001 mg to 1000 mg, preferably in doses from 0.01 mg/day to 750 mg/day,and more preferably in doses from 0.10 mg/day to 500 mg/day.

In some embodiments, the compounds provided herein act as sodium channelblockers. See, e.g., Example 154. The instant compounds, may, forexample, be useful for the treatment of neuropathic pain. Neuropathicpain, also known as nerve pain or neuropathy, is the result of nervedamage and can be caused by such diverse conditions as diabetes,shingles, cancer, HIV, multiple sclerosis and fibromyalgia, as well asphysical trauma to the nerves. According to the Neuropathy Association,an estimated 1 in 15 Americans suffer from peripheral neuropathy. Itsprevalence is particularly high among diabetes patients and incidenceincreases with age. Though neuropathic pain is a very common condition,its symptoms, including numbness, tingling, and pricking sensations,sensitivity to touch, or burning sensations, can be highly variable,making diagnosis difficult. If left untreated, neuropathy can lead topermanent nerve damage and significant disability.

Chronic neuropathic pain arises from nerves injured or damaged bysystemic disease, infection, toxins, or physical trauma. The damagednerves are in a continuous state of hyper-excitability, often due toaberrant sodium channel firing. This hyper-excitability results intransmission of abnormal pain signals from the periphery to the centralnervous system (CNS). Existing therapies that block sodium channels totreat neuropathic pain have been shown to provide effective pain relief,but are typically associated with significant unwanted CNS side effects,including dizziness, ataxia and somnolence. The compounds providedherein, may, in one or more embodiments, be able to selectively blockhyper-excitable sodium channels without causing the CNS side effectsthat limit usage of current existing therapies. Thus, in someembodiments, the instant compounds are useful in treating neuropathicpain associated with one or more of the following: diabetes, shingles,cancer, HIV, multiple sclerosis, fibromyalgia, and physical trauma tothe nerves.

The unit dosage of any given compound of the invention (again,preferably provided as part of a pharmaceutical preparation) can beadministered in a variety of dosing schedules depending on the judgmentof the clinician, needs of the patient, and so forth. The specificdosing schedule will be known by those of ordinary skill in the art orcan be determined experimentally using routine methods. Exemplary dosingschedules include, without limitation, administration five times a day,four times a day, three times a day, twice daily, once daily, threetimes weekly, twice weekly, once weekly, twice monthly, once monthly,and any combination thereof. Once the clinical endpoint has beenachieved, dosing of the composition is halted.

All articles, books, patents, patent publications and other publicationsreferenced herein are incorporated by reference in their entireties. Inthe event of an inconsistency between the teachings of thisspecification and the art incorporated by reference, the meaning of theteachings and definitions in this specification shall prevail(particularly with respect to terms used in the claims appended herein).For example, where the present application and a publicationincorporated by reference defines the same term differently, thedefinition of the term shall be preserved within the teachings of thedocument from which the definition is located.

EXAMPLES

It is to be understood that while the invention has been described inconjunction with certain preferred and specific embodiments, theforegoing description as well as the examples that follow are intendedto illustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

Example 1 Preparation of Compound 1

2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 1)

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 1) was prepared according to the following steps.

Step 1: Preparation of 3,6-dichloro-1,2,4-triazin-5-amine (Compound 2)

3,5,6-Trichloro-1,2,4-triazine (20 g, 108 mmol) was dissolved inacetonitrile (30 mL). This solution was added, slowly, to a 15% aqammonia solution (50 mL, 433 mol of NH₃) at 5-20° C. The reactionmixture was stirred for one hour and progress of the reaction wasmonitored by thin layer chromatograghy (“TLC”). After completion of thereaction, 300 mL of water was added and the reaction mass stirred for anadditional one hour at 10-15° C. The solid that precipitated wasfiltered, washed with water and dried under vacuum giving3,6-dichloro-1,2,4-triazin-5-amine (Compound 2) (16.0 g; Yield: 90%).

Step 2: Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 3)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2) (5.00 g, 30.3 mmol),2-amino-2-methylpropan-1-ol (4.05 g, 45.5 mmol) and NaHCO₃ (5.09 g, 60.6mmol) were added to a RB flask containing 50 mL of 1,4-dioxane. Thismixture was degassed for 10-15 minutes. The degassed reaction mixturewas stirred at 85-90° C. for 18-20 hours. Progress of the reaction wasmonitored by high performance liquid chromatography (“HPLC”). Thereaction mixture was allowed to attain room temp (20-25° C.) and thenfiltered (to remove inorganic salt and unreacted NaHCO₃). A 1,4-dioxanesolution was concentrated and the crude thus obtained was purified bycolumn chromatography (using DCM/MeOH as eluent) giving2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 3) (1.00 g, 15.16% yield).

Step 3: Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 1)

2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 3) (1.00 g, 4.59 mmol) and (2,3-dichlorophenyl)boronic acid(1.753 g, 9.19 mmol) were dissolved in 20 mL of 1,4-dioxane.Pd(PPh₃)₄(531 mg, 0.459 mmol), K₂HPO₄ (1.761 g, 10.11 mmol) and 5 mL ofDI water were added to the above reaction mixture. The reaction mixturewas degassed for 10-15 minutes and then stirred under heating (at 85-90°C.) for 4-6 hours. The reaction mixture was concentrated, and to it, 5mL of DI water and 10 mL of ethyl acetate, were added. The pH wasadjusted to ˜1-2 with aqueous HCl. The reaction mixture was thenfiltered through celite bed. The organic layer was separated and theaqueous layer was again washed with EtOAc (2×10 mL). The pH of theaqueous layer was adjusted to ˜9-10 using aqueous KOH and the compoundwas extracted into dichloromethane (“DCM”) (2×25 mL). The DCM solutionwas concentrated and the crude product thus obtained was purified bycolumn chromatography, giving2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(Compound 1). (1.00 g, 66.3% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 7.70(d, 1H), 7.45 (t, 1H), 7.35 (d, 1H), 6.30-7.20 (br s, 2H), 6.1-6.30 (brs, 1H), 5.1-5.3 (br s, 1H), 3.45-3.55 (d, 2H), 1.25-1.50 (s, 6H); MS(ESI) for C₁₃H₁₅C₁₂N₅O: 328.05 (MH⁺). The free base was dissolved in 4Mhydrochloric acid in 2-propanol and stirred for two hours. The mixturewas precipitated using MTBE to afford white solid as hydrochloride salt.

Example 2 Preparation of Compound 4

2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diolCompound 4

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol(Compound 4) was prepared according to the following steps.

Step 1: Preparation of2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol(Compound 5)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2) (1.5 g, 9.09 mmol),2-((2-phenyl-1,3-dioxan-5-yl)oxy)ethanamine (2.64 g, 11.64 mmol) andsodium bicarbonate (1.146 g, 13.64 mmol) were added to a round bottomflask containing 15 mL of 1,4-dioxane, and equipped with a condenser anda CaCl₂ guard tube. Nitrogen was purged into the reaction mixture for10-15 minutes and then it was stirred at 80-85° C. for 4-5 hours. Aftercompletion of the reaction, the mixture was filtered, concentrated andthe residue was heated with aqueous hydrochloric acid at 50° C. for 30minutes. The crude product was purified by column chromatography toyield2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol(Compound 5) (400 mg, 20% yield).

Step 2: Preparation of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol(Compound 4)

2-(2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol(Compound 5) (400 mg, 1.517 mmol) and (2,3-dichlorophenyl)boronic acid(492 mg, 2.58 mmol) were dissolved in 20 mL of 1,4-dioxane.Pd(PPh₃)₄(175 mg, 0.152 mmol), K₂HPO₄ (581 mg, 3.34 mmol) and 5 mL of DIwater were added to the above reaction mixture. Nitogen was purged intothe reaction mixture for 10-15 minutes and the mixture was stirred at80-85° C. for 2-3 hours. The reaction mixture was concentrated and 5 mLof DI water and 10 mL of ethyl acetate were added. The pH of thereaction mixture was adjusted to ˜1-2 with aqueous HCl and the reactionmixture was subsequently filtered through a celite bed. The organiclayer was separated and the aqueous layer was again washed with EtOAc(2×10 mL). The pH of the aqueous layer was adjusted to ˜9-10 usingaqueous KOH and the compound was extracted into DCM (2×25 mL). The DCMlayer was concentrated and the crude thus obtained was purified bycolumn chromatography giving2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)propane-1,3-diol(Compound 4). The free base was dissolved in 4M HCl in 2-propanol. Themixture was concentrated to afford the product as a hydrochloride salt(100 mg, 18% yield). ¹H NMR (500 MHz, DMSO-d₆+D₂O): δ 7.80 (d, 1H), 7.65(m, 2H), 3.8 (m, 2H), 3.6-3.3 (m, 7H); MS (ESI) for C₁₄H₁₇C₁₂N₅O₃: 374.2(MH⁺).

Example 3 Preparation of Compound 6

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6) is prepared in accordance with the following steps.

Step-1: Preparation of tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (Compound 7)

2-amino-2-methylpropan-1-ol is reacted with boc-anhydride, usingtriethylamine as base and DCM solvent to yield the tert-butyl(1-hydroxy-2-methylpropan-2-yl)carbamate (Compound 7a).

Step-2: Preparation of 2-((tert-butoxycarbonyl)amino)-2-methylpropylmethanesulfonate (Compound 8a)

Tert-butyl (1-hydroxy-2-methylpropan-2-yl)carbamate (Compound 7) isreacted with 1.2 mol equivalent of mesyl chloride using triethylamine(1.5 eq) as base, in DCM as a solvent, to afford2-((tert-butoxycarbonyl)amino)-2-methylpropyl methanesulfonate (Compound8a).

Step-3: Preparation of tert-butyl(1-(2-(benzyloxy)ethoxy)-2-methylpropan-2-yl)carbamate (Compound 9a)

2-(Benzyloxy)ethanol is mixed with NaH (1.2 eq) in THF as a solvent andto this is added, slowly, 2-((tert-butoxycarbonyl)amino)-2-methylpropylmethanesulfonate (Compound 8a) to afford the synthesis of tert-butyl(1-(2-(benzyloxy)ethoxy)-2-methylpropan-2-yl)carbamate (Compound 9a)which, is further purified by column chromatography to obtain a purecompound.

Step-4: Preparation of 2-(2-amino-2-methylpropoxy)ethanol (Compound 10)

Tert-butyl (1-(2-(benzyloxy)ethoxy)-2-methylpropan-2-yl)carbamate(Compound 9) is reacted with TFA/DCM to remove the boc-group. In asubsequent step, debenzylation is carried out, using Pd/C, under H₂pressure conditions, to afford 2-(2-amino-2-methylpropoxy)ethanol(Compound 10).

Step-5: Preparation of2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 11a)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2) (1 eq),2-(2-amino-2-methylpropoxy)ethanol (Compound 10) (1.5 eq) and NaHCO₃ (2eq) are added together, in dioxane. The reaction mixture is stirred at80-85° C. for 18-20 hours. The crude compound thus obtained is purifiedby column chromatography, to afford pure2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 11a), which is characterized by mass and ¹H NMR.

Step-6: Preparation of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6)

2-(2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 11a) is reacted, under Suzuki coupling conditions, with2,3-dichlorophenyl boronic acid, using K₂HPO₄ as base and Pd(PPh₃)₄ ascatalyst, in a dioxane/water medium at 85-90° C. The crude compound thusobtained is purified by column chromatography to afford2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6). The free base is subjected to 4M HCl in 2-propanol toobtain the HCl salt of Compound 6.

Example 3A Additional Approach for the Preparation of Compound 6

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6) was prepared in accordance with the following steps.

Step-1: Preparation of benzyl (1-hydroxy-2-methylpropan-2-yl)carbamate(Compound 7b)

2-Amino-2-methylpropan-1-ol (5 g, 89.13 mmol) was reacted with benzylchloroformate (8.61 g, 50.5 mmol), using triethylamine (7.38 g, 72.9mmol) as base in DCM solvent (50 mL) at room temperature for 3 hours.After completion of the reaction, the organic layer was washed withwater (2×20 mL) and dried over sodium sulfate. The DCM layer uponconcentration under vacuum afforded benzyl(1-hydroxy-2-methylpropan-2-yl)carbamate (Compound 7b).

Step-2: Preparation of tert-butyl2-(2-(((benzyloxy)carbonyl)-amino)-2-methylpropoxyl)acetate (Compound8b)

Benzyl (1-hydroxy-2-methylpropan-2-yl)carbamate (Compound 7b) (10 g,26.9 mmol) and tert-butylbromoacetate (5.24 g, 26.9 mmol) were added toa round bottom flask containing 30% aqueous NaOH solution (30 mL) andtoluene (50 mL). The reaction mixture was stirred for 18 hours at roomtemperature. After completion of the reaction, the toluene layer wasseparated and concentrated under vacuum to obtain a residue, which uponpurification by column chromatography yielded tert-butyl2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropoxy)acetate (Compound 8b)(4.5 g, 49.6% yield).

Step-3: Preparation of tert-butyl 2-(2-amino-2-methylpropoxy)acetate(Compound 9b)

Tert-butyl 2-(2-(((benzyloxy)carbonyl)amino)-2-methylpropoxy)acetate(Compound 8b) (4.5 g, 13.34 mmol) and 50% wet Pd/C (0.50 g, 10% w/w)were added to a round bottom flask containing 45 mL of THF and subjectedto hydrogenation for two hours. After completion of the reaction, thereaction mass was filtered through a celite bed, and the filtrate wasconcentrated under vacuum to give tert-butyl2-(2-amino-2-methylpropoxy)acetate (Compound 9b) (2.5 g, 92% yield).

Step-4: Preparation of 2-(2-amino-2-methylpropoxy)ethanol (Compound 10)

To a solution of tert-butyl 2-(2-amino-2-methylpropoxy)acetate (Compound9b) (2.5 g, 12.3 mmol) in THF (20 mL) was added LiAlH₄ (0.93 g, 24.6mmol) under a nitrogen atmosphere and the reaction mixture was stirredfor 20 hours. After completion of the reaction, a 20% sodium sulfatesolution (10 mL) and ethyl acetate (20 mL) were charged sequentially tothe reaction mixture under stirring. After stirring for 30 minutes, thereaction mixture was filtered through a celite bed. The organic layerwas separated and concentrated under vacuum to afford2-(2-amino-2-methylpropoxy)ethanol (Compound 10).

Step-5: Preparation of2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 11)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2) (1.24 g, 7.51 mmol),2-(2-amino-2-methylpropoxy)ethanol (Compound 10) (1.5 g, 11.26 mmol) andNaHCO₃ (1.26 g, 15.02 mmol) were added to a round bottom flaskcontaining 30 mL of 1,4-dioxane. The mixture was degassed for 10-15minutes. The degassed reaction mixture was stirred at 110° C. for 18-20hours. After completion of the reaction, the reaction mixture wasallowed to attain room temperature (20-25° C.) and then filtered (toremove inorganic salt and unreacted NaHCO₃). The filtrate 1,4-dioxanesolution was concentrated under vacuum and the crude thus obtained waspurified by column chromatography (using DCM/MeOH as eluent) giving2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 11) (0.30 g, 15.27% yield).

Step-6: Preparation of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6)

2-(2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 11) (0.30 g, 1.15 mmol) and (2,3-dichlorophenyl) boronic acid(0.437 g, 2.29 mmol) were dissolved in 10 mL of 1,4-dioxane, andPd(PPh₃)₄(0.083 g, 0.071 mmol), K₂HPO₄ (0.54 g, 3.1 mmol) and 5 ml of DIwater were added to the mixture. The mixture was degassed for 10-15minutes and then stirred under heating (at 85-90° C.) for 4 hours. Aftercompletion of the reaction, the reaction mass was allowed to attain roomtemperature. The reaction mixture was then filtered through a celite bedand the filtrate was concentrated under vacuum. To the residue, 20 mL ofwater was added and the product extracted into DCM (3×20 mL). The DCMsolution was concentrated and the crude was subsequently purified bycolumn chromatography (using DCM/MeOH as eluent), thereby yielding2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)ethanol(Compound 6). (0.050 g, 11.72% yield). ¹H NMR (500 MHz, DMSO-d⁶):δ7.75-7.65 (d, 1H), 7.45-7.35 (dd, 1H), 7.35-7.25 (d, 1H), 6.30-6.10 (brs, 1H), 4.65-4.50 (t, 1H), 3.65-3.55 (s, 2H), 3.50-3.30 (m, 4H),1.40-1.30 (s, 6H); MS(ESI) for C₁₅H₁₉C₁₂N₅O₂: 372.07 (MH⁺). The freebase is subjected to 4M HCl in 2-propanol to obtain the HCl salt ofCompound 6.

Example 4 Preparation of Compound 12

6-(2,3-Dichlorophenyl)-N3-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 12)

6-(2,3-Dichlorophenyl)-N3-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 12) is prepared in accordance with the following steps.

Step-1: Preparation of (((1,3-dimethoxypropan-2-yl)oxy)methyl)benzene(Compound 13)

2-(Benzyloxy)propane-1,3-diol is reacted with methyl iodide (2 eq) inthe presence of NaH (2.2 eq) as base, to afford(((1,3-dimethoxypropan-2-yl)oxy)methyl)benzene (Compound 13).

Step-2: Preparation of 1,3-dimethoxypropan-2-ol (Compound 14)

(((1,3-Dimethoxypropan-2-yl)oxy)methyl)benzene is debenzylated usingPd/C, under H₂ atmosphere to yield 1,3-dimethoxypropan-2-ol (Compound14).

Step-3: Preparation of tert-butyl2-((1,3-dimethoxypropan-2-yl)oxy)acetate (Compound 15)

1,3-Dimethoxypropan-2-ol (Compound 14) is reacted withtert-butylbromoacetate in the presence of NaH as base. The crude ispurified by column chromatography to afford tert-butyl2-((1,3-dimethoxypropan-2-yl)oxy)acetate (Compound 15).

Step-4: Preparation of 2-((1,3-dimethoxypropan-2-yl)oxy)ethanol(Compound 16)

tert-Butyl 2-((1,3-dimethoxypropan-2-yl)oxy)acetate (Compound 15) isreacted with lithium aluminum hydride (LAH) in THF to afford2-((1,3-dimethoxypropan-2-yl)oxy)ethanol (Compound 16).

Step-5: Preparation of 2-((1,3-dimethoxypropan-2-yl)oxy)ethylmethanesulfonate (Compound 17)

2-((1,3-Dimethoxypropan-2-yl)oxy)ethanol (Compound 16) is reacted withmethanesulphonyl chloride (1 eq) in the presence of triethylamine (1.2eq) as base, in DCM solvent. After completion of reaction, the resultingcompound is isolated and purified to afford2-((1,3-dimethoxypropan-2-yl)oxy)ethyl methanesulfonate (Compound 17).

Step-6: Preparation of 2-((1,3-dimethoxypropan-2-yl)oxy)ethanamine(Compound 18)

2-((1,3-Dimethoxypropan-2-yl)oxy)ethyl methanesulfonate (Compound 17) isreacted with aqueous ammonia (30%) for 16 hours. The resulting compoundis extracted using DCM and the organic layer is concentrated to afford2-((1,3-dimethoxypropan-2-yl)oxy)ethanamine (Compound 18).

Step-7: Preparation of6-chloro-N³-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 19)

A solution of 3,6-dichloro-1,2,4-triazin-5-amine (Compound 2),2-((1,3-dimethoxypropan-2-yl)oxy)ethanamine (Compound 18) (1.5 eq) andNaHCO₃ (2 eq) in 1,4-dioxane is stirred for 18-20 hours at 85-90° C.After completion of the reaction, the crude product is purified bycolumn chromatography to afford6-chloro-N³-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 19).

Step-8: Preparation of6-(2,3-dichlorophenyl)-N3-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 12)

6-Chloro-N³-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 19) is subjected to Suzuki coupling, with 2,3-dichlorophenylboronic acid, using K₂HPO₄ as base and Pd(PPh₃)₄ as catalyst, in adioxane/water medium at 85-90° C. The crude compound is purified bycolumn chromatography to afford6-(2,3-dichlorophenyl)-N³-(2-((1,3-dimethoxypropan-2-yl)oxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 12). The free base form of the compound is subjected to 4M HClin 2-propanol to afford the HCl salt (Compound 12).

Example 5 Preparation of Compound 20

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propane-1,3-diol(Compound 20)

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propane-1,3-diol(Compound 20) was prepared according to the following steps.

Step 1: Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propane-1,3-diol (Compound21)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2) (3.00 g, 18.18 mmol) and2-aminopropane-1,3-diol (2.98 g, 32.7 mmol) were dissolved in 30 mL of1,4-dioxane. NaHCO₃ (3.51 g, 41.8 mmol) was added to the above reactionmixture and followed by 10-15 minutes of degassing. The reaction mixturewas stirred at 80° C. for 8-10 hours. After completion of the reaction,the mixture was filtered (at 40-55° C.), and the organic layer wasconcentrated under vacuum to afford2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propane-1,3-diol (Compound21) (3.20 g, 80% yield).

Step 2: Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propane-1,3-diol(Compound 20)

2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)propane-1,3-diol (Compound21) (3.20 g, 14.57 mmol) and (2,3-dichlorophenyl)boronic acid (6.12 g,32.1 mmol) were dissolved in 32 mL of 1,4-dioxane. Pd(PPh₃)₄(1.684 g,1.457 mmol), K₂HPO₄ (5.58 g, 32.1 mmol) and 10 mL of DI water were addedto the above reaction mixture followed by 10-15 minutes of degassing.The degassed reaction mixture was stirred at 85-90° C. for 4-6 hours.After completion of the reaction, the reaction mass was concentrated andto it 10 mL of DI water and 20 mL EtOAc, were added. The pH was thenadjusted to ˜1-2 with aqueous HCl and the reaction mass was filteredthrough a celite bed. The organic layer was separated and the aqueouslayer was washed with EtOAc (2×10 mL). The pH of the aqueous layer wasadjusted to ˜8-9 (using aqueous KOH) and it was stirred for one hour.The precipitated compound was filtered, washed with water (10 mL), andwas dried under vacuum to afford2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propane-1,3-diol(Compound 20) (1.30 g, 27% yield) as a pale yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 7.70 (d, 1H), 7.45 (t, 1H), 7.35 (d, 1H), 5.80-7.30 (brs, 3H), 4.55-4.7 (t, 2H), 3.85-4.00 (br s, 1H), 3.50-3.60 (m, 4H); MS(ESI) for C₁₂H₁₃C₁₂N₅O₂: 330.04 (MH⁺). The free base was dissolved in 4Mhydrochloric acid in 2-propanol. The mixture was concentrated to affordthe product as the hydrochloride salt.

Example 6 Preparation of Compound 22

6-(2,3-Dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 22)

6-(2,3-Dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 22) is prepared in accordance with the following steps.Although the results associated with this approach were not satisfactorywhen carried out, the general procedure described in this example isbelieved to be nonetheless helpful as optimization of this procedureshould result in a more acceptable result.

Step-1: Preparation of tert-butyl4-(2-hydroxyethyl)piperazine-1-carboxylate (Compound 23)

tert-Butyl piperazine-1-carboxylate (1 eq) is reacted with bromoethanol(1 eq) in DMF as solvent and K₂CO₃ as base (1 eq) at 60-65° C. for 18-20hours. The crude product is purified by column chromatography to affordtert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (Compound 23).

Step-2: Preparation of tert-butyl4-(2-(((methylthio)carbonothioyl)oxy)ethyl)piperazine-1-carboxylate(Compound 24)

tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (Compound 23) isreacted with carbondisulfide (1 eq) in the presence of NaH (1 eq) asbase, in THF solvent (at 5-15° C.). After one hour, methyl iodide (1 eq)is added at 5-10° C. and the reaction is stirred for one hour at 20-25°C. After completion of the reaction, the crude product is purified bycolumn chromatography to afford tert-butyl4-(2-(((methylthio)carbonothioyl)oxy)ethyl)piperazine-1-carboxylate(Compound 24).

Step-3: Preparation of 1-(2-(trifluoromethoxy)ethyl)piperazine (Compound25)

To a suspension of 1,3-dibromo-5,5-dimehtylhydantoin (3 eq) indichloromethane is added HF-pyridine (40 eq) (at −78° C.), and then,slowly, tert-butyl4-(2-(((methylthio)carbonothioyl)oxy)ethyl)piperazine-1-carboxylate(Compound 24) (1 eq) is added at the same temperature. The reactionmixture is stirred at −78° C. for one hour and is subsequently warmed to0° C. and stirred for two hours. After completion of reaction, the crudeproduct is purified by column chromatography to afford1-(2-(trifluoromethoxy)ethyl)piperazine (Compound 25).

Step-4: Preparation of6-chloro-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 26)

A solution of 3,6-dichloro-1,2,4-triazin-5-amine (Compound 2),1-(2-(trifluoromethoxy)ethyl)piperazine (Compound 25) (1.5 eq) andNaHCO₃ (2 eq) in 1,4-dioxane is stirred for 18-20 hours at 85-90° C.After completion of reaction, the crude product is purified by columnchromatography to afford the6-chloro-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 26).

Step-5: Preparation of6-(2,3-dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 22)

6-Chloro-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 26) is coupled to 2,3-dichlorophenyl boronic acid under Suzukiconditions, using K₂HPO₄ as base and Pd(PPh₃)₄ as catalyst in adioxane/water medium at 85-90° C. The crude product is purified bycolumn chromatography to afford6-(2,3-dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 22). The free base form of the compound is subjected to 4M HClin 2-propanol to obtain the HCl salt of Compound 22.

Example 6A Additional Approach for the Preparation of Compound 22

6-(2,3-Dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 22)

6-(2,3-Dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Coumpound 22) was prepared in accordance with the following steps.

Step 1: Preparation of5-amino-6-chloro-3-N-(4-N-Boc-piperazinyl)amino-1,2,4-triazine

Schematically, the preparation of5-amino-6-chloro-3-N-(4-N-Boc-piperazinyl)amino-1,2,4-triazine wascarried out as indicated immediately below.

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (466 mg,2.82 mmol) and triethylamine (1.0 mL, 7.17 mmol), and t-Boc-piperazine(0.5675 g, 2.96 mmol) in dioxane. The mixture was heated at 95° C. for1.5 hours using a microwave. The mixture was cooled to room temperature,filtered and the white solid was washed with ethyl acetate. The organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford 872.4 mg product as solid in 98% yield. ¹H NMR (500 MHz,Chloroform-d) δ 5.38 (br, 2H), 3.76-3.68 (m, 4H), 3.44 (dd, J=6.3, 3.9Hz, 4H), 1.42 (s, 9H). LC-MS: 315.0 (MH⁺/z).

Step 2: Preparation of 3-N-piperazin-1-yl lamotrigine (Compound 79)

Schematically, the preparation of 3-N-piperazin-1-yl lamotrigine wascarried out as indicated immediately below.

A mixture of (2,3-dichlorophenyl)boronic acid (355.4 g, 1.86 mmol),5-amino-6-chloro-3-(4-N-BOC-piperazin-1-yl)amino-1,2,4-triazine (302.4mg, 0.96 mmol) and cesium carbonate (1.0591 g, 3.22 mmol) was dissolvedin dioxane/water (10 mL/2 mL), followed by addition oftetrakis(triphenylphosphine)palladium (112.6 mg, 0.097 mmol). Themixture was purged with nitrogen for a few minutes. The mixture washeated to 90° C. over 30 minutes, and kept at 90° C. for 5.5 hours. Themixture was cooled to room temperature and concentrated to remove theorganic solvent. The residue was dissolved in water and extracted withdichloromethane (3×40 mL). The combined organic solution was dried overanhydrous sodium sulfate, filtered and the filtrate was concentrated.The residue was purified with flash column chromatography on silica gelusing 1-10% methanol/dichloromethane. The product was purified againwith flash column chromatography on silica gel using 30-55% ethylacetate/hexane to afford intermediate (222.5 mg, 55%).

The intermediate (222.5 mg) was dissolved in 1.5 mL of methanol and 0.5mL of 4 N hydrochloride in dioxane was added. The mixture was stirred atroom temperature for 4 hours and 40 minutes. More of 4 N hydrochloridein dioxane (0.3 mL) was added. The mixture was stirred at roomtemperature for 17.5 hours. The mixture was concentrated to remove thesolvents. The residue was dried under high vacuum to afford the finalproduct as HCl salt (21.6.1 mg). ¹H NMR (500 MHz, DMSO-d₆) δ 9.61 (s,2H), 8.99 (br, 1H), 8.07 (br, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.54 (t,J=7.9 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 4.04 (s, 4H), 3.265 (s, 4H).LC-MS: 325.0 (MH⁺/z).

The HCl salt (68.3 mg) was mixed with saturated potassium carbonatesolution and extracted with dichloromethane (3×20 mL). The combinedorganic solution was washed with brine, dried over anhydrous soldiumsulfate, and concentrated to afford the product as a free base (47.6mg). ¹H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J=2.0 Hz and 8.0 Hz,1H), 7.37-7.31 (m, 2H), 4.69 (br, 2H), 3.86 (m, 4H), 2.95 (t, J=5.0 Hz,4H). LC-MS: 325.0 (MH⁺/z).

Step 3: Preparation of6-(2,3-dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 22)

Schematically, the preparation of Compound 22 was carried out asindicated immediately below.

6-(2,3-dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 79) (100 mg, 0.308 mmol), 1-bromo-2-(trifluoromethoxy)ethane(59.3 mg, 0.308 mmol), and N,N-dimethylaminopyridine (37.6 mg, 0.308mmol) were dissolved in dioxane (5 ml). The solution was heated at 105°C. on microwave reactor for 3 h. LC-MS analysis indicated the startingmaterial was consumed completely. Solids were filtered off and filtratewas concentrated on Rotavap under reduced pressure. The resultingresidue was loaded to a samplet and subject to flash chromatography onBiotage by using a gradient of 0-5% MeOH with DCM. Fractions containingdesired product were collected, combined, and concentrated.

After drying under high vacuo, product was afforded as white powder (24mg, 95.2% purity, 18% yield). ¹H-NMR (500 MHz, CDCl₃) δ 7.60 (1H, dd, J₁5.0 Hz, J₂=2.0 Hz), 7.36 (2H, m), 4.79 (2H, bs), 4.14 (2H, t, J=5.5 Hz),3.93 (4H, bs), 2.77 (2H, t, J=5.5 Hz), 2.63 (4H, t, J=5.0 Hz). LC-MS[ESI-MH⁺]: m/z 437.

Example 7 Preparation of Compound 27

1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27)

1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27) was prepared according to the following steps.

Step 1: Preparation of 2-(benzyloxy)-3-(trifluoromethoxy)propan-1-ol(Compound 28)

2-(Benzyloxy)propan-1,3-diol (25 g, 137 mmol),1-trifluoromethyl-1,2-benziodoxol-3(1H)-one (4.34 g, 13.7 mmol) andbis(1,1,1-trifluoro-N-(trifluoromethyl)sulfonyl)methylsulfonamido)zinc(4.29 g, 6.85 mmol) were added to a round bottom flask containing 25 mLof chloroform. The reaction mixture was stirred at 30-32° C. for 20hours under nitrogen atmosphere. The reaction was monitored by ¹⁹F NMR.After completion of the reaction, the mixture was concentrated and thecrude product obtained was purified by column chromatography (usingethyl acetate/hexane as eluant) giving2-(benzyloxy)-3-(trifluoromethoxy)propan-1-ol (Compound 28) (2.0 g, 58%yield).

Step 2: Preparation of 2-(benzyloxy)-3-(trifluoromethoxy)propylmethanesulfonate (Compound 29)

2-(Benzyloxy)-3-(trifluoromethoxy)propan-1-ol (Compound 28) (2.1 g, 8.4mmol) was dissolved in 20 mL of dichloromethane, in a round bottomflask. To this was added triethylamine (1.189 g, 1.1.7 mmol) under anitrogen atmosphere. The reaction was cooled to 0-5° C. and thenmethanesulfonyl chloride (1.154 g, 10.0 mmol) was added drop wise to thereaction using an addition funnel, maintaining the reaction temperatureat 5-10° C. Post addition, the reaction was stirred at 20-25° C. for twohours. After completion of reaction, 10% aqueous ammonium chloride (30ml) was added to the reaction and it was stirred for five minutes. Theorganic layer was separated and washed with saturated sodium bicarbonatesolution (20 mL) and water (10 mL) respectively. The organic layer wasdried over anhydrous sodium sulfate and concentrated to obtain the crudeproduct which was purified by column chromatography (eluent ethylacetate/hexane mixture) to give 2-(benzyloxy)-3-(trifluoromethoxy)propylmethanesulfonate (Compound 29) (2.0 g, 72.7% yield).

Step 3: Preparation of1-(2-(benzyloxy)-3-(trifluoromethoxy)propyl)piperazine (Compound 30)

2-(Benzyloxy)-3-(trifluoromethoxy)propyl methanesulfonate (Compound 29)(0.650 g, 1.98 mmol), piperazine (1.705 g, 19.8 mmol) and K₂CO₃ (1.368g, 9.90 mmol) were added to a round bottom flask containing 25 mL ofdimethylformamide under a nitrogen atmosphere. The reaction mixture wasstirred at 60-65° C. for six hours. The reaction progress was monitoredby HPLC and after completion of reaction, the reaction mixture wascooled to 20-25° C. and filtered through sintered funnel to removesalts. The filtrate was concentrated under vacuum to obtain the crudeproduct, which was purified by column chromatography (usingdichloromethane/methanol as eluent) to give1-(2-(benzyloxy)-3-(trifluoromethoxy)propyl)piperazine (Compound 30).(0.33 g, 52% yield).

Step-4: Preparation of1-(piperazine-1-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 31)

1-(2-(Benzyloxy)-3-(trifluoromethoxy)propyl)piperazine (Compound 30)(0.33 g, 1.03 mmol) and 50% wet Pd/C (0.07 g, 10% w/w) were added to around bottom flask containing 25 mL of methanol and subjected tohydrogenation, for 20 hours. After completion, the reaction was filteredthrough a celite bed, and the filtrate was concentrated to give1-(piperazine-1-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 31) (0.18g, 76.7% yield).

Step-5: Preparation of1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 32)

3,6-Dichloro-1,2,4-triazin-5-amine (0.108 g, 0.657 mmol),1-(piperazine-1-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 31) (0.18g, 0.789 mmol) and sodium bicarbonate (0.083 g, 0.986 mmol) were addedto a round bottom flask containing 10 mL of 1,4-dioxane, and equippedwith a condenser and calcium chloride guard tube. Nitrogen was purgedinto the reaction mixture for 10-15 minutes and the reaction mass washeated under stirring at 80-85° C. for 5-6 hours. After completion ofthe reaction, the reaction mass was allowed to reach room temperatureand was then filtered to remove salts. The filtrate was concentratedunder vacuum. The obtained residue (crude) was purified by columnchromatography (using dichloromethane/methanol as an eluent) to give1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 32) (78 mg, 33% yield).

Step-6: Preparation of1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27)

1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 32) (78 mg, 0.219 mmol) and (2,3-dichlorophenyl)boronic acid(104 mg, 0.547 mmol) were dissolved in 10 mL of 1,4-dioxane.Pd(PPh₃)₄(18 mg, 0.015 mmol), K₂HPO₄ (76 mg, 0.437 mmol) and 5 mL ofwater were added to the above reaction mixture. The reaction mixture wasdegassed for 10-15 minutes and then stirred under heating (at 85-90° C.)for 4-6 hours. After completion of the reaction, the reaction mixturewas allowed to attain room temperature and was filtered through celitebed. The filtrate was concentrated under vacuum to remove the organicsolvent. To the remaining crude, 10 mL of water was added and theproduct was extracted into dichloromethane (3×10 mL). Thedichloromethane solution was concentrated and the crude thus obtainedwas purified by preparative thin layer chromatography to give1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27) (18 mg, 18% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.60 (m,1H), 7.38 (m, 2H), 4.05 (m, 4H), 3.85-3.95 (m, 4H), 3.6-3.7 (m, 1H),2.75 (m, 2H), 2.5-2.6 (m, 4H); ¹⁹F NMR: δ −60.954 (s, OCF₃); MS (ESI)for C₁₇H₁₉C₁₂F₃N₆O₂: 467.05 (M⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol (2 mL) and stirred for one hour. The mixturewas concentrated and product was precipitated by addition of MTBE. Theprecipitated product was filtered and the cake was dried to afford paleyellow solid as hydrochloride salt (15 mg). 1H NMR (500 MHz, DMSO-d6): δ7.80 (m, 1H), 7.52 (m, 1H), 7.39 (m, 1H), 4.70-4.50 (m, 2H), 4.40-4.30(m, 1H), 4.20-4.05 (m, 2H), 3.60-3.32 (m, 4H), 3.30-3.15 (m 4H); ¹⁹FNMR: δ −58.929 (s, OCF₃).

Example 7A Additional Approach for the Preparation of Compound 27

1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27)

1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27) can also be prepared in accordance with the followingsteps.

Step-1: Preparation of 2-(benzyloxy)-3-(trityloxy)propan-1-ol (Compound33)

2-(Benzyloxy)propane-1,3-diol is reacted with 0.7 eq of trityl chloridein DCM as solvent and triethylamine (1 eq) as base. After completion ofreaction, the crude product is purified by column chromatography toafford 2-(benzyloxy)-3-(trityloxy)propan-1-ol (Compound 33).

Step-2: Preparation of 2-(benzyloxy)-3-(trityloxy)propylmethanesulfonate (Compound 34)

2-(Benzyloxy)-3-(trityloxy)propan-1-ol (Compound 33) is reacted withmethanesulfonyl chloride (1 eq) in DCM as solvent and triethylamine (1.2eq) as base to afford 2-(benzyloxy)-3-(trityloxy)propyl methanesulfonate(Compound 34).

Step-3: Preparation of benzyl4-(2-(benzyloxy)-3-(trityloxy)propyl)piperazine-1-carboxylate (Compound35)

Benzyl piperazine-1-carboxylate (1 eq) is reacted with2-(benzyloxy)-3-(trityloxy)propyl methanesulfonate (Compound 34) (1 eq)in DMF solvent and K₂CO₃ as base (1 eq) at 60-65° C. for 18-20 hours.The resulting crude product is purified by column chromatography toafford benzyl4-(2-(benzyloxy)-3-(trityloxy)propyl)piperazine-1-carboxylate (Compound35).

Step-4: Preparation of benzyl4-(2-(benzyloxy)-3-hydroxypropyl)piperazine-1-carboxylate (Compound 36)

Selective trityl deprotection of benzyl4-(2-(benzyloxy)-3-(trityloxy)propyl)piperazine-1-carboxylate (35) iscarried out at pH ˜3 using aqueous HCl. Crude compound resulting fromthe reaction is purified by column chromatograph to yield benzyl4-(2-(benzyloxy)-3-hydroxypropyl)piperazine-1-carboxylate (Compound 36).

Step-5: Preparation of benzyl4-(2-(benzyloxy)-3-(((methylthio)carbonothioyl)oxy)propyl)piperazine-1-carboxylate(Compound 37)

Benzyl 4-(2-(benzyloxy)-3-hydroxypropyl)piperazine-1-carboxylate(Compound 36) is reacted with carbondisulfide (1 eq) in the presence ofNaH (1 eq) as base in THF solvent at 5-15° C. After one hour, to thereaction mixture is added methyl iodide (1 eq) at 5-10° C. and thereaction mixture is stirred for one hour at 20-25° C. After completionof the reaction, the crude product is purified by column chromatographyto afford the benzyl4-(2-(benzyloxy)-3-(((methylthio)carbonothioyl)oxy)propyl)piperazine-1-carboxylate(Compound 37).

Step-6: Preparation of benzyl4-(2-(benzyloxy)-3-(trifluoromethoxy)propyl)piperazine-1-carboxylate(Compound 38)

To a suspension of 1,3-dibromo-5,5-dimehtylhydantoin (3 eq) indichloromethane is added HF-pyridine (40 eq) at −78° C., followed by theslow addition of benzyl4-(2-(benzyloxy)-3-(((methylthio)carbonothioyl)oxy)propyl)piperazine-1-carboxylate(Compound 37) (1 eq) at the same temperature. The reaction mixture isstirred at −78° C. for one hour and subsequently is warmed to 0° C. andstirred at the same temperature for two hours. After completion of thereaction, the crude product is purified by column chromatography toafford benzyl4-(2-(benzyloxy)-3-(trifluoromethoxy)propyl)piperazine-1-carboxylate(Compound 38).

Step-7: Preparation of1-(piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 31)

Benzyl-4-(2-(benzyloxy)-3-(trifluoromethoxy)propyl)piperazine-1-carboxylate(Compound 38) is subjected to hydrogenation reaction conditions usingPd/C in a H₂ atmosphere to afford1-(piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 31).

Step-8: Preparation of1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 32)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2),1-(piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol (Compound 31) (1.5eq) and NaHCO₃ (2 eq) are added to a 1,4-dioxane solution and thereaction is carried out for 18-20 hours at 85-90° C. After completion ofthe reaction, the crude product is purified by column chromatography toafford1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 32).

Step-9: Preparation of1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27)

1-(4-(5-Amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 32) is subjected to Suzuki coupling reaction with2,3-dichlorophenyl boronic acid using K₂HPO₄ as base and Pd(PPh₃)₄ ascatalyst in a dioxane/water medium at 85-90° C. The crude compound thusobtained is purified by column chromatography to afford1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27). The free base of the compound is subjected to 4M HCl in2-propanol to obtain the HCl salt of Compound 27.

Example 8 Preparation of Compound 39

3-(((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 39)

3-(((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 39) is prepared in accordance with the following steps.

Step-1: Preparation of 2-(2,3-dihydroxypropoxy)isoindoline-1,3-dione(Compound 40)

N-Hydroxy-phthalimide is reacted with 3-bromo-propane-1,2-diol in thepresence of K₂CO₃ as base in DMF solvent, the crude compound is thenpurified by column chromatography to afford2-(2,3-dihydroxypropoxy)isoindoline-1,3-dione (Compound 40).

Step-2: Preparation of 3-(aminooxy)propane-1,2-diol (Compound 41)

2-(2,3-Dihydroxypropoxy)isoindoline-1,3-dione (Compound 40) is subjectedto hydrazine hydrate in ethanol and the reaction mixture is heated atreflux temperature for four hours. The crude compound is purified bycolumn chromatography to afford 3-(aminooxy)propane-1,2-diol (Compound41).

Step-3: Preparation of3-(((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 42)

A solution of 3,6-dichloro-1,2,4-triazin-5-amine (Compound 2),3-(aminooxy)propane-1,2-diol (Compound 41) (1.5 eq) and NaHCO₃ (2 eq) in1,4-dioxane is stirred for 18-20 hours at 85-90° C. After completion ofthe reaction, the crude product is purified by column chromatography toafford3-(((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 42).

Step-4: Preparation of3-(((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 39)

3-(((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 42) is coupled to 2,3-dichlorophenyl boronic acid under Suzukiconditions, using K₂HPO₄ as base and Pd(PPh₃)₄ as catalyst in adioxane/water medium at 85-90° C. The crude product is purified bycolumn chromatography to afford3-(((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)oxy)propane-1,2-diol(Compound 39). The free base form of the compound is subjected to 4M HClin 2-propanol to obtain the HCl salt of the compound (Compound 39).

Example 9 Preparation of Compound 43

4-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 43)

4-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 43) is prepared in accordance with the following steps.

Step-1: Preparation of4-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 44)

A mixture of 3,6-dichloro-1,2,4-triazin-5-amine (Compound 2),4-amino-1-methoxybutan-2-ol (1.5 eq) and NaHCO₃ (2 eq) in 1,4-dioxane isstirred for 18-20 hours at 85-90° C. After completion of the reaction,the crude product is purified by column chromatography to afford4-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 44).

Step-2: Preparation of4-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 43)

4-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 44) is coupled to 2,3-dichlorophenyl boronic acid under Suzukiconditions, using K₂HPO₄ as base and Pd(PPh₃)₄ as catalyst in adioxane/water medium at 85-90° C. The crude product is purified bycolumn chromatography to afford4-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-1-methoxybutan-2-ol(Compound 43). The free base form of the compound is subjected to 4M HClin 2-propanol to obtain the HCl salt of the compound (Compound 43).

Example 10 Preparation of Compound 45

6-(2,3-Dichlorophenyl)-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 45)

6-(2,3-Dichlorophenyl)-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 45) was prepared according to the following steps.

Step 1: Preparation of6-chloro-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 46)

3,6-Dichloro-1,2,4-triazin-5-amine (Compound 2) (54.3 mg, 0.329 mmol)and 2-(2-(trifluoromethoxy)ethoxy)ethanamine (798 mg, 4.60 mmol) wereadded to a round bottom flask, containing 8 mL of 1,4-dioxane. Sodiumbicarbonate (414 mg, 4.93 mmol) was added to the above reaction mixtureand the mixture was degassed for 10-15 minutes. The reaction mixture wasstirred under heating at 80-85° C. for 8-10 hours. After completion ofthe reaction, the mixture was allowed to attain room temp (20-25° C.)and was thereafter filtered to remove salts. The filtrate wasconcentrated under vacuum and the crude thus obtained was purified bycolumn chromatography (using dichloromethane/methanol as eluant) to give6-chloro-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 46) (540 mg, 54% yield).

Step 2: Preparation of6-(2,3-dichlorophenyl)-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 45)

6-Chloro-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 46) (200 mg, 0.66 mmol) and (2,3-dichlorophenyl)boronic acid(253 mg, 1.32 mmol) were dissolved in 12 mL of 1,4-dioxane.Tetrakis(triphenylphosphine)palladium (0) (77 mg, 0.066 mmol),dipotassium phosphate (230 mg, 1.32 mmol) and 3 ml of water were addedto the above reaction mixture and de-gassed for 10-15 minutes. Thereaction mixture was stirred under heating at 85-90° C. for 4-6 hours(maintaining nitrogen atmosphere all through). After completion of thereaction, the reaction mass was allowed to attain room temperature, andthen filtered through a celite bed. The filtrate was concentrated undervacuum to remove the organic solvent. To the crude remaining, 10 mL ofwater was added and the product was extracted into dichloromethane (3×10mL). The dichloromethane solution was concentrated and the crude thusobtained was purified by column chromatography (usingdichloromethane/methanol eluent) to give6-(2,3-dichlorophenyl)-N³-(2-(2-(trifluoromethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 45). (41 mg, 15% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.85 (m,1H), 7.45 (m, 1H), 7.35 (m, 1H), 4.21 (m, 2H), 3.73 (m, 2H), 3.58 (m2H), 3.48 (m, 2H); ¹⁹F NMR: δ −58.806 (s, OCF₃); MS (ESI) forC₁₄H₁₄C₁₂F₃N₅O₂: 412.06 (M⁺). The free base was dissolved in 4Mhydrochloride in 2-propanol (2 mL) and was stirred for one hour. Themixture was concentrated and product was precipitated by addition ofmethyl tert-butylether. The obtained solid was filtered and dried toafford an off-white product as the hydrochloride salt (40 mg). ¹H NMR(500 MHz, DMSO-d₆+D₂O): δ 7.72 (m, 1H), 7.60-7.45 (m, 2H), 4.18 (m, 2H),3.76 (m, 2H), 3.65 (m 2H), 3.55 (m, 2H); ¹⁹F NMR: δ −58.828 (s, OCF₃).

Example 11 Sodium Channel Blockage of Test Compounds

The potency of test compounds (e.g., compounds prepared in accordancewith Examples 1-9 and 13-25) to block Na+ channels is measuredelectrophysiologically using isolated rat dorsal root ganglion cells invitro. Currents are measured using the whole-cell variant of the patchclamp method. I_(Na) is elicited by a pulse to −20 mV from a holdingpotential of −120 mV or −70 mV to measure blockade at the inactivatedstate (pulse duration of 40 ms), Peak inward current is measured forI_(Na). Pacing rates of 0.1, 3 and Hz are examined. Increasingconcentrations of test compounds are added to the cells in a cumulativemanner to generate a concentration-response relationship which isutilized to calculate the IC₅₀.

Example 12 Neuropathic Pain Model

The efficacy of test compounds (e.g., compounds prepared in accordancewith Examples 1-9 and 13-25) in reducing mechanical allodynia isassessed in the chronic constriction injury model in rats. Male SD ratsare briefly anesthetized under pentobarbital anesthesia and surgery isperformed following the Bennett model of sciatic nerve ligation wherethe left sciatic nerve is loosely ligated with four chromic gut sutures.7-14 days post-surgery, rats that are clearly allodynic were randomizedto treatment groups (n-10 rats/group). Mechanical allodynia is evaluatedusing the von Frey up-down method, 30 minutes before and at 1 and 2 hrafter a single dose of test dose or Gabapentin. Aminobenzotriazole (100mg/kg p.o.) is dosed orally 16-24 hours prior to treatment with testcompounds.

Example 13 Preparation of Compound 47

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 47)

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 47) was prepared according to the following steps.

Step 1: Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 48)

3,6-Dichloro-1,2,4-triazin-5-amine (2.00 g, 12.12 mmol) and2-amino-2-methylpropane-1,3-diol (1.53 g, 14.55 mmol), Dioxane (30 mL)and sodium bicarbonate (2.04 g, 24.25 mmol) were added to a round bottomflask. Nitrogen gas was purged into the reaction mixture for 10-15minutes and the reaction mass was heated under stirring at 120-125° C.for 20 hours. After completion of the reaction, the reaction mass wascooled to room temperature and filtered to remove salts. The filtratedioxane solution was concentrated under vacuum to obtain the crude,which was purified by column chromatography (using DCM/Methanol aseluent) to give2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 48) (0.80 g, 28.20% yield).

Step 2: Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 47)

2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 48) (0.80 g, 3.42 mmol) and (2,3-dichlorophenyl)boronic acid(1.11 g, 5.82 mmol) were dissolved in 16 mL of 1,4-dioxane.Pd(PPh₃)₄(0.396 g, 0.342 mmol), K₂HPO₄ (1.193 g, 6.85 mmol) and 10 mL ofDI water were added to the above reaction mixture. The reaction mixturewas degassed for 10-15 minutes and then stirred 90° C. for 4-6 hours.After completion of the reaction, the reaction mass was allowed toattain room temperature. The cooled reaction mass was filtered through acelite bed and the filtrate was concentrated under vacuum. To the crudethus obtained, 20 mL of water was added and the product was extractedinto DCM (3×20 mL). The DCM solution was concentrated, dried and thecrude product was purified by column chromatography to give2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropane-1,3-diol(Compound 47) (0.50 g, 42.4% yield). The free base (130 mg) wasdissolved in 4M hydrochloride in 2-propanol and stirred for one hour.The mixture was concentrated to afford a pale yellow solid as thehydrochloride salt (140 mg). ¹H NMR (500 MHz, DMSO-d₆+D₂O): δ 7.85 (d,1H), 7.60-7.50 (m, 2H), 3.55-3.65 (br s, 4H), 1.35-1.40 (s, 3H); MS(ESI) for C₁₃H₁₅C₁₂N₅O₂: 344.05 (MH⁺).

Example 14 Preparation of Compound 49

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 49)

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 49) was prepared according to the following steps.

Step 1: Preparation2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 50)

3,6-Dichloro-1,2,4-triazin-5-amine (0.50 g, 3.03 mmol) and2-amino-3-(2-methoxyethoxy)-2-methylpropan-1-ol (0.72 g, 4.39 mmol),N,N-diisopropylethylamine (1.96 g, 15.15 mmol) and 5 mL of DMSO wereadded to round bottom flask. The resulting reaction mixture was stirredunder heating at 125° C. for 20 hours. At the end of reaction time, thereaction mixture was allowed to attain room temperature and 10 mL waterwas added to it. The product was extracted using DCM (3×20 mL). Thecrude product obtained upon evaporation of DCM was purified by columnchromatography (using DCM/Methanol as eluent) affording2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 50) (0.35 g, 39.60% yield).

Step 2: Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 49)

2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 50) (0.35 g, 1.20 mmol) and (2,3-dichlorophenyl)boronic acid(0.389 g, 2.04 mmol) were dissolved in 10 mL of 1,4-dioxane.Pd(PPh₃)₄(0.139 g, 0.12 mmol), K₂HPO₄ (0.418 g, 2.399 mmol) and 5 mL ofDI were added to the above reaction mixture. The reaction mixture wasdegassed for 10-15 minutes and then stirred under heating (at 85-90° C.)for 4 hours. After completion of the reaction, reaction mass was allowedto cool to room temperature. The reaction mixture was filtered through acelite bed and concentrated under vacuum. To the residue, 20 mL of waterwas added and the product was extracted into DCM (3×20 mL). The DCMsolution was concentrated and the crude thus obtained was purified bycolumn chromatography to give2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-methoxyethoxy)-2-methylpropan-1-ol(Compound 3) (0.140 g, 29% yield). ¹H NMR (500 MHz, DMSO-d₆): δ 7.70 (d,1H), 7.45 (m, 1H), 7.35 (d, 1H), 6.15-7.30 (br s, 2H), 5.90-6.00 (s,1H), 5.05-5.20 (s, 1H), 3.65-3.75 (d, 1H), 3.80-3.40 (m, 8H), 3.20-3.30(s, 3H), 1.30-1.35 (s, 3H); MS (ESI) for C₁₆H₂₁C₁₂N₅O₃: 402.08 (MH⁺).The free base was dissolved in 4M hydrochloride in 2-propanol andstirred for one hour. The mixture was concentrated to afford pale yellowsolid as hydrochloride salt (65 mg).

Example 15 Preparation of Compound 51

6-(2,3-Dichlorophenyl)-N3-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 51)

6-(2,3-Dichlorophenyl)-N³-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 51) was prepared according to the following steps.

Step 1: Preparation of6-chloro-N³-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 52)

3,6-Dichloro-1,2,4-triazin-5-amine (0.50 g, 3.03 mmol) and7-methyl-2,5,9,12-tetraoxatridecan-7-amine (0.805 g, 3.64 mmol),N,N-diisopropylethylamine (1.958 g, 15.15 mmol) and 5 mL of DMSO wereadded to round bottom flask. The resulting reaction mixture was stirredunder heating at 125° C. for 20 hours. After completion of the reaction,the reaction mixture was cooled to room temperature and 20 mL water wasadded to it. The product was extracted using DCM (3×20 mL). The crudeproduct obtained upon evaporation of DCM was purified by columnchromatography (using DCM/Methanol as eluent) affording6-chloro-N³-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 52) (0.5 g, 47.2% yield).

Step 2: Preparation of6-(2,3-dichlorophenyl)-N³-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 51)

6-Chloro-N3-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 52) (0.5 g, 1.429 mmol) and (2,3-dichlorophenyl)boronic acid(0.464 g, 2.43 mmol) were dissolved in 10 mL of 1,4-dioxane.Pd(PPh₃)₄(0.083 g, 0.071 mmol), K₂HPO₄ (0.498 g, 2.86 mmol) and 5 mL ofDI water were added to the above reaction mixture. The reaction mixturewas degassed for 10-15 minutes and then stirred under heating (at 85-90°C.) for 4 hours. After completion of the reaction, the reaction mass wasallowed to attain room temperature. The reaction mixture was filteredthrough a celite bed and the filtrate was concentrated under vacuum. Tothe residue 20 mL of water was added and the product extracted into DCM(3×20 mL). The DCM solution was concentrated and the crude uponpurification by column chromatography (using DCM/Methanol as eluent)yielded6-(2,3-dichlorophenyl)-N³-(7-methyl-2,5,9,12-tetraoxatridecan-7-yl)-1,2,4-triazine-3,5-diamine(Compound 51) (0.140 g, 21.28% yield). ¹H NMR (500 MHz, CDCl₃): δ7.50-7.60 (d, 1H), 7.30-7.40 (m, 2H), 5.65-5.85 (br s, 1H), 4.90-4.60(s, 2H), 3.85-3.90 (m, 2H), 3.80-3.50 (m, 10H), 3.45-3.30 (s, 6H),1.40-1.30 (s, 3H); MS (ESI) for C₁₉H₂₇C₁₂N₅O₄: 460.16 (MH⁺). The freebase was dissolved in 4M hydrochloride in 2-propanol and stirred for onehour. The mixture was concentrated to afford pale yellow solid ashydrochloride salt (35 mg).

Example 16 Preparation of Compound 53

6-(2,3-Dichlorophenyl)-N3-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 53)

6-(2,3-Dichlorophenyl)-N³-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine (Compound 53) was preparedaccording to the following steps.

Step 1: Preparation of6-chloro-N³-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine (Compound 54)

3,6-Dichloro-1,2,4-triazin-5-amine (70 mg 0.424 mmol) and2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-amine (500 mg,2.039 mol), N,N-diisopropyl-ethylamine (5 mL) and 2 mL of 1,4-dioxanewere added to a round bottom flask. The reaction mixture was degassedfor 10-15 minutes and stirred under heating at 80° C. for 3 days. Aftercompletion of the reaction, the reaction mass was allowed to cool toroom temperature (25° C.). The reaction mass was concentrated undervacuum, and the crude compound upon purification by columnchromatography yielded6-chloro-N³-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine (Compound 54). (130 mg,81% yield).

Step 2: Preparation of6-(2,3-dichlorophenyl)-N³-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 53)

6-Chloro-N³-(2-methyl-1-(2-(2-(trifluoromethoxy) ethoxy) ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine (Compound 54) (240 mg, 0.642mmol) and (2,3-dichlorophenyl)boronic acid (208 mg, 1.092 mmol) weredissolved in 8 mL of 1,4-dioxane. Pd(PPh₃)₄(37 mg, 0.0328 mmol), K₂HPO₄(246 mg, 1.413 mmol) and 4 mL of DI water were added to the abovereaction mixture. The reaction mixture was degassed for 10-15 minutesand then stirred under heating (at 85-90° C.) for 4 hours. Aftercompletion of the reaction, the reaction mass was cooled to roomtemperature and was filtered through a celite bed. The filtrate wasconcentrated under vacuum, and to the residue 20 mL of water was addedand the product was extracted into DCM (3×20 mL). The DCM solution wasconcentrated and the crude upon purification by column chromatography(using MTBE/Hexane as eluent) yielded6-(2,3-dichlorophenyl)-N³-(2-methyl-1-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 53) (45 mg, 14.4% yield). The free base was dissolved in 4Mhydrochloride in 2-propanol and stirred for one hour. The mixture wasconcentrated to afford a pale brown solid as the hydrochloride salt (50mg). ¹H NMR (500 MHz, CDCl₃+D₂O): δ 7.60 (d, 1H), 7.40-7.30 (m, 2H),4.10 (m, 2H), 3.80 (m, 2H), 3.70 (m, 4H), 3.60 (s, 2H), and 1.60-1.50(s, 6H). MS (ESI) for C₁₈H₂₂C₁₂F₃N₅O₃: 484.12 (MH⁺).

Example 17 Preparation of Compound 55

(R)-1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 55)

(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 55) was prepared according to the following steps.

Step 1: Preparation of(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 56)

3,6-Dichloro-1,2,4-triazin-5-amine ((1000 mg, 6.13 mmol) and(R)-1-ethoxy-3-(piperazin-1-yl)propan-2-ol (1500 mg, 7.973 mol),1,4-dioxane (20 mL) and sodium bicarbonate (1000 mg 12.16 mmol) wereadded to a round bottom flask. Nitrogen gas was purged into the reactionmixture for 10-15 minutes, following which the reaction mass was stirredat 80-85° C. for 8 hours (under an inert atmosphere). After completionof the reaction, the reaction mass was allowed to come to roomtemperature and it was filtered to remove salts. The filtrate wasconcentrated under vacuum and MTBE (10 mL) was added to residue withstirring for 30 minutes, which afforded a solid product. Upon filteringand drying, the obtained product was(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 56) (1300 mg, 67% yield).

Step 2: Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 55)

(R)-1-(4-(5-Amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 56) (600 mg, 1.894 mmol) and (2,3-dichlorophenyl)boronic acid(976 mg, 5.11 mmol) were dissolved in 10 mL of 1,4-dioxane.Pd(PPh₃)₄(109 mg, 0.095 mmol), K₂HPO₄ (726 mg, 1.14 mmol) and 4 mL of DIwater were added to the above reaction mixture. The reaction mixture wasdegassed for 1.0-15 minutes and then stirred under heating (at 85-90°C.) for 4 hours. After completion of the reaction, the reaction mass wascooled to room temperature and filtered through a celite bed. Thefiltrate was concentrated under vacuum whereupon 20 mL of water was thenadded to the residue. The product was extracted into DCM (3×20 mL). TheDCM solution was concentrated and the crude compound upon purificationby column chromatography (using DCM/methanol as eluent) yielded(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 55) (250 mg, 30.9% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.60 (d,1H), 7.45-7.30 (m, 2H), 4.70 (br s, 2H) 4.0-3.8 (m, 5H), 3.60-3.40 (m,4H), 2.80-2.70 (m, 2H), 2.60-2.45 (m, 2H), 2.30 (m, 1H) and 1.30-1.20(t, 3H). MS (ESI) for C₁₈H₂₂C₁₂F₃N₅O₃: 427.12 (MH⁺). The free base wasdissolved in 4M hydrochloride in 2-propanol and stirred for one hour.The mixture was concentrated to afford off white solid as hydrochloride,salt (250 mg).

Example 18 Preparation of Compound 57

6-(2,3-Dichlorophenyl)-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 57)

6-(2,3-Dichlorophenyl)-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 57) was prepared according to the following steps.

Step 1: Preparation of6-chloro-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 58)

To a solution of 2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethanamine (720mg, 3.6 mmol) in 1,4-dioxane (10 mL) was added5-amino-3,6-dichloro-triazine (500 mg, 3.0 mmol). The reaction mixturewas then charged with sodium bicarbonate (500 mg, 6.0 mmol). Thereaction mixture was stirred at 90° C. for 8 hours. Ethyl acetate (10mL) was added into the reaction mixture. The suspension was passedthrough a celite bed and the filtrate was evaporated to obtain the crudeproduct. The crude upon purification by flash chromatography yielded6-chloro-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 58) (0.7 g, 70% yield).

Step 2: Preparation of6-(2,3-dichlorophenyl)-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 57)

A suspension of6-chloro-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 58) (700 mg, 2.1 mmol), (2,3-dichlorophenyl)boronic acid (690mg, 3.6 mmmol), and K₂HPO₄ (820 mg, 4.7 mmol) in 1,4-dioxane:water (2:1,15 mL) was purged with nitrogen gas for 15 minutes. The reaction mixturewas charged with Pd(PPh₃)₄(250 mg, 0.21 mmol) and heated to 90° C. for 3hours. Ethyl acetate (10 mL) was added into the reaction mixture. Thesuspension was passed through a celite bed and the filtrate wasconcentrated under vacuum. The crude upon purification by flashchromatography yielded6-(2,3-dichlorophenyl)-N³-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 57) (150 mg, 17% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.57 (dd,1H), 7.36 (dd, 1H), 7.32-7.35 (m, 1H), 6.24 (t, 1H), 6.21 (bs, 1H), 4.94(bs, 2H), 4.00 (t, 2H), 3.68-3.72 (m, 10H). 19F NMR (CDCl₃): −82.3 ppm.MS (ESI) for C₁₆H₁₉C₁₂F₂N₅O₃: 438 (MH⁺). The free base (150 mg) wasdissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

Example 19 Preparation of Compound 59

6-(2,3-Dichlorophenyl)-N³-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 59)

6-(2,3-Dichlorophenyl)-N³-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 59) was prepared according to the following steps.

Step-1: Preparation of6-chloro-N³-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 60)

To a solution of 1-(difluoromethoxy)-2-methylpropan-2-amine (400 mg, 2.8mmol) in DMSO (10 mL) was added 5-amino-3,6-dichloro-triazine (120 mg,0.7 mmol). The reaction mixture was then charged with DIPEA (0.6 mL, 3.6mmol) and was stirred at 120° C. for 18 hours. After completion of thereaction, the reaction mixture was concentrated. The crude thus obtainedwas dissolved in 10 mL of ethyl acetate and was washed sequentially withwater (2×50 mL) and brine (30 mL). The ethyl acetate layer was driedover sodium sulfate and concentrated to afford6-chloro-N³-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 60) (200 mg, 99% yield).

Step 2: Preparation of6-(2,3-dichlorophenyl)-N³-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 59)

A suspension of6-chloro-N³-(1-(difluoromethoxy)-2-methylpropan-2-yl)-1,2,4-triazine-3,5-diamine(Compound 60) (700 mg, 2.1 mmol), (2,3-dichlorophenyl)boronic acid (690mg, 3.6 mmol), and K₂HPO₄ (820 mg, 4.7 mmol) in 1,4-dioxane:water (2:1,15 mL) was purged with nitrogen gas for 15 minutes. The reaction mixturewas charged with Pd(PPh₃)₄ (250 mg, 0.21 mmol) and heated to 90° C. for3 hours. After completion of the reaction, 10 mL of ethyl acetate wasadded into the reaction mixture and it was filtered through a celitebed. The crude obtained, upon evaporation of the solvent, was purifiedby flash chromatography affording6-(2,3-dichlorophenyl)-N3-(2-(2-(2-(difluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 59) (150 mg, 17% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.57 (dd,1H), 7.37 (dd, 1H), 7.33-7.38 (m, 1H), 6.24 (t, 1H), 6.09 (bs, 1H), 4.85(bs, 2H), 4.14 (s, 2H), 1.49 (s, 6H). ¹⁹F NMR (CDCl₃): −82.4 ppm. MS(ESI) for C₁₄H₁₅C₁₂F₂N₅O: 378 (MH⁺). The free base (150 mg) wasdissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

Example 20 Preparation of Compound 61

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(Compound 61)

2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(compound 61) was prepared according to the following steps.

Step 1: Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(Compound 62)

To a solution of 2-amino-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(510 mg, 2.4 mmol) in DMSO (2 mL) was added5-amino-3,6-dichloro-triazine (200 mg, 1.2 mmol). The reaction mixturewas then charged with DIPEA (1 mL, 6.0 mmol) and was stirred at 120° C.for 18 hours. The reaction mixture was concentrated and the crude uponpurification by flash chromatography yielded2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(Compound 62) (0.2 g, 48% yield).

Step 2: Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(compound 61)

A suspension of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(Compound 62) (200 mg, 0.5 mmol), (2,3-dichlorophenyl)boronic acid (190mg, 1.0 mmol), and cesium carbonate (420 mg, 1.3 mmol) in1,4-dioxane:water (2:1, 15 mL) was purged with nitrogen gas for 15minutes. The reaction mixture was charged with Pd(PPh₃)₄(34 mg, 0.03mmol) and heated to 90° C. for 6 hours. Ethyl acetate (10 mL) was addedinto the reaction mixture. The suspension was passed through a plug ofcelite and the filtrate was concentrated under vacuum to afford thecrude product. Crude upon purification by flash chromatography yielded2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-((2-fluorobenzyl)oxy)-2-methylpropan-1-ol(Compound 61) (50 mg, 19% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.59 (dd,1H), 7.34-7.38 (m, 3H), 7.22-7.24 (m, 1H), 7.09 (t, 1H), 7.01 (t, 1H),5.6 (bs, 1H), 4.8 (bs, 2H), 4.64 (s, 2H), 3.82-3.84 (m, 1H), 3.65-3.71(m, 4H), 1.43 (s, 3H). ¹⁹F NMR (CDCl₃): δ −118. MS (ESI) forC₂₁H₂₀C₁₂FN₅O₂: 452 (MH⁺). The free base (50 mg) was dissolved in 2 mLof 4N hydrochloride in 2-propanol. The mixture was concentrated toafford product as hydrochloride salt.

Example 21 Preparation of Compound 63

(S)-1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-ol(Compound 63)

(S)-1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-ol,(Compound 63) was prepared according to the following steps.

Step 1: Preparation of(S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-ol (Compound 64)

To a solution of (S)-pyrrolidin-3-ol (400 mg, 4.6 mmol) in DMSO (2 mL)were added 5-amino-3,6-dichloro-triazine (660 mg, 4.0 mmol) and sodiumbicarbonate (670 mg, 8.0 mmol). The reaction mixture was stirred at 120°C. for 18 hours. Upon attaining completion, the reaction mass wasdiluted with 10 mL of water. The precipitated product was filtered,washed with ethyl acetate (2×20 mL), and was dried under vacuumaffording (S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-ol(Compound 64) (430 mg, 49% yield).

Step 2: Preparation of(S)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-ol(Compound 63)

A suspension of(S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-ol (Compound 64)(430 mg, 1.9 mmol), (2,3-dichlorophenyl)boronic acid (647 mg, 3.4 mmol),and K₂HPO₄ (764 mg, 4.4 mmol) in 1,4-dioxane:water (2:1, 6 mL) waspurged with nitrogen gas for 15 minutes. The reaction mixture wascharged with Pd(PPh₃)₄(230 mg, 0.2 mmol) and heated to 90° C. for 3hours. Ethyl acetate (10 mL) was added into the reaction mixture. Thesuspension was passed through a plug of celite. The crude thus obtained,after evaporation of the solvent, was purified by flash chromatographyyielding(S)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-ol(Compound 63) (120 mg, 18% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.70 (dd,1H), 7.44 (t, 1H), 7.35 (dd, 1H), 6.7 (bs, 2H), 4.95 (d, 1H), 4.36 (bs,1H), 3.50-3.54 (m 4H), 1.95-2.00 (m, 1H), 1.88-1.95 (m, 1H). MS (ESI)for C₁₃H₁₃C₁₂N₅O: 326 (MH⁺). The free base (120 mg) was dissolved in 2mL of 4N hydrochloride in 2-propanol. The mixture was concentrated toafford product as hydrochloride salt.

Example 22 Preparation of Compound 65

(2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65)

(2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65) was prepared according to the following steps.

Step 1: Preparation of (2S,4R)-methyl1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 66)

To a solution of (2S,4R)-methyl 4-hydroxypyrrolidine-2-carboxylate (1.3g, 7.2 mmol) in DMSO (2 mL) were added 5-amino-3,6-dichloro-triazine(700 mg, 4.2 mmol) and triethylamine (3.8 mL, 38.2 mmol). The reactionmixture was stirred at 120° C. for 18 hours. Excess triethylamine wasremoved by evaporation under vacuum and the crude upon purification byflash chromatography yielded (2S,4R)-methyl1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 66) (500 mg, 43% yield).

Step 2: Preparation of (2S,4R)-methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate,hydrochloride salt (compound 65)

A suspension of (2S,4R)-methyl1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 66) (200 mg, 0.7 mmol), (2,3-dichlorophenyl)boronic acid (230mg, 1.2 mmol), and cesium carbonate (520 mg, 1.6 mmol) in1,4-dioxane:water (2:1, 6 mL) was purged with nitrogen gas for 15minutes. The reaction mixture was charged with Pd(PPh₃)₄(40 mg, 0.05mmol) and heated to 90° C. for 3 hours. Upon attaining completion, 10 mLethyl acetate was added into the reaction mixture. The suspension waspassed through a plug of celite. The crude obtained, after evaporationof the solvent, was purified by flash chromatography yielding(2S,4R)-methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65) (100 mg, 35% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.66 (dd,1H), 7.42 (t, 1H), 7.34 (d, 1H), 4.85 (bs, 2H), 4.65 (bs, 1H), 4.60 (s,1H), 4.54 (bs, 1H), 3.82 (bs, 2H), 3.73 (s, 3H), 2.36 (bs, 1H), 2.17 (s,1H). MS (ESI) for C₁₅H₁₅C₁₂N₅O₃: 384 (MH⁺). The free base (100 mg) wasdissolved in 2 mL of 4N hydrochloride in 2-propanol. The mixture wasconcentrated to afford product as hydrochloride salt.

Example 23 Preparation of Compound 67

(3R,5S)-1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)-methyl)pyrrolidin-3-ol(Compound 67)

(3R,5S)-1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol(Compound 67) was prepared according to the following steps.

Step 1: Preparation of(3R,5S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol(Compound 68)

To a solution of (3R,5S)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol(300 mg, 1.3 mmol) in DMSO (2 mL) were added5-amino-3,6-dichloro-triazine (150 mg, 0.9 mmol) and triethylamine (1.0mL, 7.2 mmol). The reaction mixture was stirred at 120° C. for 4 hours.The reaction mixture was evaporated to remove excess triethylamine. Theresidue was taken in 30 mL of ethyl acetate, washed sequentially withwater (2×10 mL) and brine (10 mL). The ethyl acetate layer was driedover sodium sulfate, concentrated under vacuum to afford the crudeproduct. The crude upon purification by flash chromatography yielded(3R,5S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol(Compound 68) (250 mg, 78% yield).

Step 2: Preparation of(3R,5S)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol(Compound 67)

A suspension of(3R,5S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)methyl)pyrrolidin-3-ol(Compound 68) (250 mg, 0.7 mmol), (2,3-dichlorophenyl)boronic acid (230mg, 1.2 mmol), and cesium carbonate (500 mg, 1.5 mmol) in1,4-dioxane:water (2:1, 6 mL) was purged with nitrogen gas for 15minutes. The reaction mixture was charged with Pd(PPh₃)₄(40 mg, 0.05mmol) and heated to 90° C. for 3 hours. Ethyl acetate (10 mL) was addedinto the reaction mixture. The suspension was passed through a plug ofcelite. The crude, generated after evaporation of the solvent, waspurified by flash chromatography yielding(3R,5S)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-5-(((2-fluorobenzyl)oxy)-methyl)pyrrolidin-3-ol(Compound 67) (60 mg, 18% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.59 (dd,1H), 7.34-7.38 (m, 3H), 7.22-7.24 (m, 1H), 7.09 (t, 1H), 7.01 (t, 1H),4.67-4.69 (m, 4H), 4.58-4.59 (m, 3H), 3.78-3.86 (m, 4H), 2.37-2.42 (m,1H), 2.13-2.18 (m, 1H). ¹⁹F NMR (470 MHz, CDCl₃): δ −118. MS (ESI) forC₂₁H₂₀C₁₂FN₅O₂: 464 (MH⁺). The free base (60 mg) was dissolved in 2 mLof 4N hydrochloride in 2-propanol. The mixture was concentrated toafford product as hydrochloride salt.

Example 24 Preparation of Compound 69

(R)-1-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yi)amino)-2-methylpropoxy)-3-methoxypropan-2-ol (Compound 69)

(R)-1-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol(Compound 69) is prepared in accordance with the following steps.

Step-1: Preparation of(R)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol(Compound 70)

3,6-Dichloro-1,2,4-triazin-5-amine (1.00 eq),(R)-1-(2-amino-2-methylpropoxy)-3-methoxypropan-2-ol (1.5 eq) and sodiumbicarbonate (2 eq) are added to a 1,4-dioxane solution and degassed for5-10 minutes; the reaction is then carried out for 18-20 hours at 85-90°C. After completion of the reaction, the crude product is purified bycolumn chromatography to afford(R)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol(Compound 70).

Step-2: Preparation of(R)-1-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol(Compound 69)

(R)-1-(2-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol(Compound 70) is subjected to Suzuki coupling reaction with(2,3-dichlorophenyl)boronic acid using K₂HPO₄ as base and Pd(PPh₃)₄ ascatalyst in a mixture of dioxane/water at 85-90° C. The crude obtained,after routine work-up, upon purification by column chromatographyaffords(R)-1-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-methoxypropan-2-ol(Compound 69). The free base of the compound is subjected to 4M HCl in2-propanol to obtain the HCl salt of Compound 69.

Example 25 Preparation of Compound 71

(R)-1-(((S)-1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 71)

(R)-1-(((S)-1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 71) is prepared in accordance with the following steps.

Step-1: Preparation of(R)-1-(((S)-1-(5-Amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 72)

3,6-Dichloro-1,2,4-triazin-5-amine (1.00 eq),(R)-1-methoxy-3-((S)-pyrrolidin-3-yloxy)propan-2-ol (1.5 eq) and sodiumbicarbonate (2 eq) are added to 1,4-dioxane and degassed for 5-10minutes. The reaction is performed by stirring at 85-90° C. for 18-20hours. After completion of the reaction, a routine work-up affords crudewhich upon purification by column chromatography affords(R)-1-(((S)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 72).

Step-2: Preparation of(R)-1-(((S)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 71)

(R)-1-(((S)-1-(5-Amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 72) is subjected to a Suzuki coupling reaction with(2,3-dichlorophenyl)boronic acid using K₂HPO₄ as a base and Pd(PPh₃)₄ asa catalyst in a dioxane/water mixture, at 85-90° C. The crude compoundthus obtained is purified by column chromatography to afford(R)-1-(((S)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 71). The free base of the compound is subjected to 4M HCl in2-propanol to obtain the HCl salt of Compound 71.

Example 26 Preparation of Compound 73

(R)-1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxypropan-2-ol(Compound 73)

(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 73) was prepared in accordance with the following steps.

Step-1: Preparation of(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 74)

To a solution of (R)-1-isopropoxy-3-(piperazin-1-yl)propan-2-ol (2.45 g,12.12 mmol) in 1,4-dioxane (10 mL) was added5-amino-3,6-dichloro-triazine (2.0 g, 12.12 mmol). The reaction mixturewas then charged with sodium bicarbonate (3.06 mL, 36.4 mmol). Thereaction mixture was stirred at 90° C. for 5 hours. Evaporation of thesolvent and purification of the residue by flash chromatography yielded(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 74) (1.5 g, 37.8% yield).

Step-2: Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 73)

A suspension of(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 74) (570 mg, 1.7 mmol), (2,3-dichlorophenyl)boronic acid (1.2g, 6.4 mmol), and cesium carbonate (1.2 g, 3.79 mmol) in1,4-dioxane:water (2:1, 6 mL) was purged with nitrogen gas for 15minutes. The reaction mixture was charged with Pd(PPh₃)₄(100 mg, 0.09mmol) and heated to 90° C. for 3 hours. Ethyl acetate (10 mL) was addedinto the reaction mixture. The suspension was passed through a plug ofcelite. The resulting crude, after evaporation of the solvent, waspurified by flash chromatography and yielded(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 73) (260 mg, 38% yield). ¹H NMR (500 MHz, CDCl₃): δ 7.59 (dd,1H), 7.30-7.4 (m, 2H), 4.70 (bs, 2H), 3.85-3.95 (m, 5H), 3.59-3.65 (m,1H), 3.39-3.49 (ABq, 2H), 3.25 (bs, 1H), 2.69-2.75 (m, 2H), 2.51-2.59(m, 3H), 2.45 (dd, 1H), 1.19 (d, 6H). MS (ESI) for C₁₉H₂₆C₁₂N₆O₂: 442(MH⁺). The free base (160 mg) was dissolved in 2 mL of 4N hydrochloridein 2-propanol. The mixture was concentrated to afford product ashydrochloride salt.

Example 27 Preparation of Compound 75

(R)-1-((1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75)

(R)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75) is prepared according to the following steps

Step 1: Preparation of(R)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 76)

(R)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol

Chemical Formula: C₁₀H₁₆ClNO₃

Molecular Weight: 289.719

To a solution of (R)-1-(azetidin-3-yloxy)-3-methoxypropan-2-ol (1.0equiv.) in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine(1.0 equiv.). The reaction mixture is then charged with sodiumbicarbonate (3.0 equiv) and stirred at 90° C. Evaporation of the solventand purification of the residue by flash chromatography affords(R)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 76).

Step-2: Preparation of(R)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75)

To a suspension of(R)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 76) (1.0 equiv.), (2,3-dichlorophenyl)boronic acid (1.7equiv.), and cesium carbonate (3.3 equiv.) in 1,4-dioxane:water is addedPd(PPh₃)₄(0.05 equiv.) and heated to 90° C. The crude produced afterevaporation of the solvent and purification by flash chromatographyaffords(R)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol,(Compound 75). The free base is dissolved in 2 mL of 4N hydrochloride in2-propanol. The mixture is concentrated to afford product ashydrochloride salt.

Example 28 Preparation of Compound 77

(S)-1-(3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 77)

(S)-1-(3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 77) is prepared according to the following steps.

Step 1: Preparation of(S)-1-(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 78)

To a solution of (S)-1-(3-aminoazetidin-1-yl)-3-methoxypropan-2-ol (1.0equiv.) in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine(1.0 equiv.). The reaction mixture is then charged with sodiumbicarbonate (3.0 equiv) and stirred at 90° C. Evaporation of the solventand purification of the residue by flash chromatography affords(S)-1-(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 78).

Step-2: Preparation of(S)-1-(3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 77)

To a suspension of(S)-1-(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 78) (1.0 equiv.), (2,3-dichlorophenyl)boronic acid (1.7equiv.), and cesium carbonate (3.3 equiv.) in 1,4-dioxane:water is addedPd(PPh₃)₄(0.05 equiv.) and heated to 90° C. The crude after evaporationof the solvent upon purification by flash chromatography affords(S)-1-(3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 77).

Example 29 Preparation of Compound 78

Preparation of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-tert-butoxypropan-2-ol(Compound 78)

2-(tert-butoxymethyl)oxirane (45.9 mg, 0.352 mmol) was added to asuspension of6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 79) (46 mg, 0.141 mmol) in ethanol (0.4 mL). The resultingmixture was heated in a microwave oven at 120° C. for 30 minutes. Thesolvent was removed under reduced pressure and the crude product waspurified by flash chromatography (90:10 dichloromethane/methanol) toafford(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-tert-butoxypropan-2-ol(Compound 78) (31 mg, 48.1%) as an off white foam. ¹H NMR (500 MHz,Chloroform-d): δ 7.57 (dt, J=1.5, 7.50 Hz, 1H), 7.40-7.29 (m, 2H), 4.84(bs, 2H), 3.90 (m, 5H), 3.45-3.35 (m, 2H), 2.71 (dt, J=5.0, 10.7 Hz,2H), 2.54 (m, 2H), 2.50 (ddd, J=1.2, 4.1, 12.4 Hz, 1H), 1.21 (s, 9H). MS(EI) for C₂₀H₂₈C₁₂N₆O₂: 455 (MH⁺).

Example 30 Preparation of Compound 80

Preparation of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutylmethoxy)propan-2-ol(Compound 80)

2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutylmethoxy)propan-2-ol(Compound 80) was prepared according to the following steps.

Step 1: Preparation of6-(2,3-Dichlorophenyl)-3-{4-[(2S)-oxiran-2-ylmethyl]piperazin-1-yl}-1,2,4-triazin-5-amine(Compound 81)

(S)-2-(chloromethyl)oxirane (0.263 mL, 3.37 mmol) was added to asuspension of6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 79) (995 mg, 3.06 mmol) in ethanol (15 mL). The resultingmixture was stirred at room temperature for 33 hours and the solvent wasremoved under reduced pressure. The residue was purified by flashchromatography (90:10 dichloromethane/methanol), suspended intetrahydrofurane (10 mL) and treated with 4M sodium hydroxide (0.467 mL,1.867 mmol). The resulting solution was stirred at room temperature for4 hours. Water was added and the solvent was removed under reducedpressure. The residue was dissolved in dichloromethane (100 mL) andwashed with sodium chloride saturated solution (50 mL). The organiclayer was dried over anhydrous magnesium sulfate and the solvent wasremoved under reduced pressure to yield6-(2,3-Dichlorophenyl)-3-{4-[(2S)-oxiran-2-ylmethyl]piperazin-1-yl}-1,2,4-triazin-5-amine(Compound 81) (0.66 g, 93%) as a light yellow foam that was used withoutfurther purification. ¹H NMR (500 MHz, Chloroform-d): δ 7.58 (dd,J=2.06, 7.6 Hz, 1H), 7.41-7.32 (m, 2H), 4.78 (bs, 2H), 3.95 (d, J=5.3Hz, 4H), 3.18 (dq, J=3.2, 6.9 Hz, 1H), 2.89-2.80 (m, 2H), 2.73 (dt,J=5.1, 10.7 Hz, 2H), 2.62 (dt, J=5.2, 10.9 Hz, 2H), 2.54 (dd, J=2.7, 5.0Hz, 1H), 2.34 (dd, J=6.9, 13.3 Hz, 1H). MS (EI) for C₁₆H₁₈C₁₂N₆O: 381(MH⁺).

Step 2: Preparation of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutylmethoxy)propan-2-ol(Compound 80)

A mixture of6-(2,3-Dichlorophenyl)-3-{4-[(2S)-oxiran-2-ylmethyl]piperazin-1-yl}-1,2,4-triazin-5-amine(Compound 89) (60 mg, 0.157 mmol), cyclobutylmethanol (0.3 mL, 3.56mmol) and 50% sodium hydroxide (13 L, 0.157 mmol) was heated in amicrowave oven at 120° C. for 30 minutes. Excess of cyclobutylmethanolwas removed under reduced pressure and the crude product was purified byreverse phase preparative HPLC using a Phenomenex Gemini, 10 □m, C18,150×21.2 mm column at a flow rate of 20 mL/min and mobile phases of 85%water, 15% acetonitrile (with 10 mM NH4OH) and 45% water, 55%acetonitrile (with 10 mM NH4OH) to afford(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutylmethoxy)propan-2-ol(Compound 80) (4.2 mg, 5.17%) as a white solid. ¹H NMR (500 MHz,Chloroform-d): δ 7.59 (dd, J=7.5, 2.2 Hz, 1H), 7.42-7.33 (m, 2H), 4.76(bs, 2H), 3.99 (m, 5H), 3.54-3.43 (m, 4H), 2.78 (m, 2H), 2.60 (td,J=13.2, 11.8, 6.2 Hz, 4H), 2.51 (m, 1H), 2.13-2.02 (m, 2H), 2.00-1.87(m, 2H), 1.80-1.69 (m, 3H). MS (EI) for C₂₁H₂₈C₁₂N₆O₂: 467 (MH⁺).

The free base was dissolved in acetonitrile and treated with 1Nhydrochloric acid in ethyl ether (50 μL). Solvents were removed underreduced pressure to generate the hydrochloride salt of the tittlecompound as a white solid.

Example 31 Preparation of Compound 83

Preparation of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclopropylmethoxy)propan-2-ol(Compound 83)

The title compound was prepared following the same method as for Example30, but using cyclopropylmethanol. From 60 mg of6-(2,3-dichlorophenyl)-3-{4-[(2S)-oxiran-2-ylmethyl]piperazin-1-yl}-1,2,4-triazin-5-amine(Compound 81), 9.0 mg of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclopropylmethoxy)propan-2-ol(Compound 83) were obtained as a white solid (11% yield). ¹H NMR (500MHz, Chloroform-d): δ 7.58 (dd, J=2.1, 7.5 Hz, 1H), 7.41-7.32 (m, 2H),4.78 (bs, 2H), 4.00 (ddd, J=3.3, 5.1, 10.2 Hz, 1H), 4.00-3.89 (m, 4H),3.55 (dd, J=4.1, 9.9 Hz, 1H), 3.49 (dd, J=5.7, 9.9 Hz, 1H), 3.35 (d,J=6.9 Hz, 2H), 2.75 (dt, J=5.0, 10.7 Hz, 2H), 2.56 (tt, J=5.8, 10.8 Hz,3H), 2.48 (dd, J=3.6, 12.5 Hz, 1H), 1.80 (bs, 1H), 1.15-1.03 (m, 1H),0.59-0.52 (m, 2H), 0.26-0.19 (m, 2H). MS (EI) for C₂₀H₂₆C₁₂N₆O₂: 453(MH⁺).

The free base was dissolved in acetonitrile and treated with 1Nhydrochloric acid in ethyl ether (100 μL). Solvents were removed underreduced pressure to generate the hydrochloride salt of the tittlecompound as a white solid.

Example 32 Preparation of Compound 84

Preparation of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutyloxy)propan-2-ol(Compound 84)

The title compound was prepared following the same method as for Example30, but using cyclobutanol. From 103 mg of6-(2,3-dichlorophenyl)-3-{4-[(2S)-oxiran-2-ylmethyl]-piperazin-1-yl}-1,2,4-triazin-5-amine(Compound 81), 45 mg of(2S)-1-{4-[5-Amino-6-(2,3-di-chlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutyloxy)propan-2-ol(Compound 84) were obtained as a white solid (32% yield). ¹H NMR (500MHz, Chloroform-d): δ 7.59 (dd, J=2.1, 7.5 Hz, 1H), 7.42-7.33 (m, 2H),4.78 (bs, 2H), 4.03-3.91 (m, 1H), 3.92 (m, 5H), 3.46-3.31 (m, 2H),2.78-2.70 (m, 2H), 2.55 (ddd, J=3.9, 7.7, 13.3 Hz, 3H), 2.46 (dd, J=3.6,12.5 Hz, 1H), 2.28-2.18 (m, 2H), 2.03-1.89 (m, 2H), 1.77-1.66 (m, 2H),1.52 (qt, J=8.0, 10.53 Hz, 1H). MS (EI) for C₂₀H₂₆C₁₂N₆O₂: 453 (MH⁺).

The free base was dissolved in acetonitrile and treated with 1Nhydrochloric acid in ethyl ether (0.7 mL). Solvents were removed underreduced pressure to generate the hydrochloride salt of the tittlecompound as a white solid.

Example 33 Preparation of Compound 85

Preparation of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclopentyloxy)propan-2-ol(Compound 85)

The title compound was prepared following the same method as for Example30, but using cyclopentanol. From 99 mg of6-(2,3-dichlorophenyl)-3-{4-[(2S)-oxiran-2-ylmethyl]-piperazin-1-yl}-1,2,4-triazin-5-amine(Compound 81), 4.3 mg of(2S)-1-{4-[5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclopentyloxy)propan-2-ol(Compound 85) were obtained as a white solid (3.3% yield). ¹H NMR (500MHz, Chloroform-d) δ 7.59 (dd, J=2.1, 7.6 Hz, 1H), 7.42-7.32 (m, 2H),4.75 (bs, 2H), 3.95 (dq, J=2.4, 3.1, 5.7 Hz, 1H), 3.93 (m, 5H),3.50-3.38 (m, 2H), 2.74 (dt, J=5.0, 10.7 Hz, 2H), 2.66-2.50 (m, 2H),2.51-2.43 (m, 2H), 1.79-1.63 (m, 7H), 1.58-1.52 (m, 2H). MS (EI) forC₂₁H₂₈C₁₂N₆O₂: 467 (MH⁺).

Example 34 Preparation of Compound 86

Preparation of3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-ol

The following is a general scheme useful for the preparation of3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-1-alkylylpropan-1-ols(exemplified for the cyclobutylpropan-1-ol shown above):

Step 1: Preparation of benzyl4-(3-(methoxy(methyl)amino)-3-oxopropyl)piperazine-1-carboxylate is asFollows

A 100 mL flask is charged with N-methoxy-N-methylacrylamide (0.576 g, 5mmol), dry tetrahydrofuran (20 mL) and benzyl piperazine-1-carboxylate(1.211 g, 5.50 mmol), and the mixture heated at 40° C. for 16 hours toafford a solution of benzyl4-(3-(methoxy(methyl)amino)-3-oxopropyl)piperazine-1-carboxylate (1.677g, 5.00 mmol) in tetrahydrofuran (10 mL), which is carried forwarddirectly to the next step.

Step 2: Preparation of benzyl4-(3-cyclobutyl-3-oxopropyl)piperazine-1-carboxylate is Carried Out asFollows

A solution of benzyl4-(3-(methoxy(methyl)amino)-3-oxopropyl)piperazine-1-carboxylate (1.677g, 5.00 mmol) in tetrahydrofuran (20 mL) is cooled to 0° C., whereupon asolution of cyclobutylmagnesium bromide, 0.5 M in tetrahydrofuran (15.0mL, 7.50 mmol) is added dropwise. After consumption of starting Weinrebamide, the mixture is quenched with saturated ammonium chloride (10 mL),and partitioned between ethyl acetate (100 mL), and water (50 mL). Theorganic layer is washed with 0.5 M sodium dihydrogen phosphate (2×30mL), 1 M sodium bicarbonate (20 mL), dried (sodium sulfate) andconcentrated to afford crude benzyl4-(3-cyclobutyl-3-oxopropyl)piperazine-1-carboxylate (assumed 5.00mmol), which may be carried forward to the next step without furtherpurification.

Step 3: Preparation of benzyl4-(3-cyclobutyl-3-hydroxypropyl)piperazine-1-carboxylate is Carried Outas Set Forth Below

The crude benzyl 4-(3-cyclobutyl-3-oxopropyl)piperazine-1-carboxylate(assumed 5.00 mmol) is taken up in methanol (20 mL), and treated withsodium borohydride (0.95 g, 25 mmol) at room temperature for theappropriate time. After the reaction is complete, the mixture ispartitioned between ethyl acetate (100 mL) and 1 M sodium carbonate (50mL), and the organic layer is dried (sodium sulfate), filtered andconcentrated. Purification by chromatography on silica may be expectedto afford benzyl4-(3-cyclobutyl-3-hydroxypropyl)piperazine-1-carboxylate.

Step 4: Preparation of 1-cyclobutyl-3-(piperazin-1-yl)propan-1-ol is asDescribed Below

A solution of benzyl4-(3-cyclobutyl-3-hydroxypropyl)piperazine-1-carboxylate (0.66 g, 2.0mmol) and acetic acid (0.23 mL, 4.00 mmol) in ethanol (20 mL) is addedto 10% palladium hydroxide on carbon (0.14 g, 0.10 mmol), and themixture hydrogenated at room temperature for sufficient time to removethe carboxybenzyl group. The mixture is filtered and concentrated toafford crude 1-cyclobutyl-3-(piperazin-1-yl)propan-1-ol (assumed 2.00mmol) which is carried forward to the next step without furtherpurification.

Step 5: Preparation of3-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-olis Described Below

A 25 mL flask is charged with1-cyclobutyl-3-(piperazin-1-yl)propan-1-ol, bis acetate salt (0.190 g,0.60 mmol) and 3,6-dichloro-1,2,4-triazin-5-amine (0.082 g, 0.50 mmol),dry 1,4-dioxane (1 mL) and triethylamine (0.21 mL, 1.50 mmol), and themixture heated in a microwave vial at 120° C. for 45 min. The mixture isconcentrated and the residue partitioned between dichloromethane (50 mL)and 1 M sodium carbonate (25 mL). The organic layer is dried (sodiumsulfate), filtered and concentrated to afford crude3-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-ol(assumed 0.50 mmol), which might be carried forward to the next stepwithout further purification.

Step 6: Preparation of3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-olis as Follows

A 20 mL septumed screw-capped vial is charged withtetrakis(triphenylphosphine)-palladium (116 mg, 0.10 mmol), capped witha septum, and purged with nitrogen, whereupon solutions of3-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-ol(assumed 0.50 mmol) in nitrogen sparged dioxane (7 mL) and(2,3-dichlorophenyl)boronic acid (191 mg, 1.00 mmol) and cesiumcarbonate (505 mg, 1.55 mmol) in nitrogen-sparged water (2.3 mL) areadded, and the stirred mixture heated in a heat block at 90° C. for theappropriate time to consume the chlorotriazine. The mixture isconcentrated and chromatographed to afford3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-1-cyclobutylpropan-1-ol.

Example 35 Preparation of Compound 87 Preparation of6-(2,3-dichlorophenyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 87)

Preparation of 2,2,2-trifluoroethyl methanesulfonate

To an approximately 0.2 M solution of 2,2,2-trifluoroethanol (2 mL, 27.4mmol) in DCM (100 mL) containing 20% excess TEA (2.25 mL, 32.9 mmol) at0-10° C. was added a 10% excess mesyl chloride (1.5 ml, 0.961 mmol) overa period of 5-10 min. Stirring for an additional 10-15 min completed thereaction. The reaction mixture was transferred to a separatory funnelwith the addition of more DCM. The mixture was extracted by cold 10%hydrochloric acid, saturated sodium bicarbonate solution and brine.Drying the solution followed by removal of solvent gave product as clearoil. ¹H-NMR (500 MHz, DMSO-d₆) δ 3.362 (3H, s), 4.945 (2H, q, J=8.5 Hz).

Preparation of6-(2,3-dichlorophenyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2,4-triazin-5-amine

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (50 mg,0.154 mmol), 2,2,2-trifluoroethyl methanesulfonate (110 mg, 0.615 mmol)and triethylamine (86 μL) were dissolved in dioxane (3 mL). The mixturewas heated at 200° C. for 6 h. Solvent was removed and residue wassubject to flash column chromatography to give a product as white solid(10 mg, 99% purity, 16% yield). LC-MS [ESI-MH⁺]: m/z 407; ¹H-NMR (500MHz, DMSO-d₆) δ 2.687 (4H, t, J=8.5 Hz), 3.239 (2H, q, J=10.0 Hz), 3.738(4H, m), 6.510-6.800 (1H, br), 7.358 (1H, dd, J₁=1.5 Hz, J₂=8.0 Hz),7.448 (1H, t, J=2.5 Hz), 7.710 (1H, dd, J₁=1.5 Hz, J₂=8.0 Hz).

The product was dissolved in methanol and 4 equiv. HCl aqueous solutionwas added. Methanol was removed under reduced pressure. The remainingsolution was frozen and lyophilized for 2 days to afford hydrochloridesalt.

Example 36 Preparation of Compound 88 Preparation of6-(2,3-dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 88)

6-(2,3-dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (100 mg,0.308 mmol), 1-bromo-2-(trifluoromethoxy)ethane (59.3 mg, 0.308 mmol),and N,N-dimethylpyridine (37.6 mg, 0.308 mmol) were dissolved in dioxane(5 mL). The solution was heated at 105° C. on microwave reactor for 3 h.Solids were filtered off and filtrate was concentrated on Rotavap underreduced pressure. The resulting residue was purified by silica gelcolumn. Fractions containing desired product were collected, combined,and concentrated. After drying under high vacuo, product was afforded aswhite powder (24 mg, 95.2% purity, 18% yield). LC-MS [ESI-MH⁺]: m/z 437.¹H-NMR (500 MHz, CDCl₃) δ 2.63 (4H, t, J=5.0 Hz), 2.77 (2H, t, J=5.5Hz), 3.93 (4H, bs), 4.14 (2H, t, J=5.5 Hz), 4.79 (2H, bs), 7.36 (2H, m),7.60 (1H, dd, J=5.0 Hz, J₂=2.0 Hz).

The product was dissolved in methanol and 4 equiv. HCl aqueous solutionwas added. Methanol was removed under reduced pressure. The remainingsolution was frozen and lyophilized for 2 days to afford hydrochloridesalt.

Example 37 Preparation of Compound 89 Preparation of2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol(Compound 89)

Preparation of 2,2-(benzylimino)diethanol: Benzyl amine (5.09 mL, 46.7mmol) and 2-chloroethanol (9.38 mL, 140 mmol) were added together in a250-mL flask. A solid sodium carbonate (7.42 g, 70 mmol) was addedfollowing with water (2 mL). The reaction was heating up in an oil bathto 112° C. for 3 hrs. The reaction mixture was cool down andco-evaporated with MeOH (30 mL×3). The residue was then dissolved in DCMand filtrated. The remaining residue was washed with DCM 3 times. Thecombined DCM was concentrated under reduced pressure and gave anoil-like product (4.78 g, 53% yield) after high vacuo drying. LC-MS(ESI, MH⁺) 196.2; ¹H NMR (500 MHz, CDCl₃) δ 2.74 (4H, t, J=5.0 Hz), 3.65(4H, t, J=5.0 Hz), 3.72 (2H, s), 7.28-7.37 (5H, m).

Preparation of bis-(2-chloro-ethyl)-(4-benzyl)-amine:2,2-(Benzylimino)diethanol (2.78 g, 14.2 mmol) was dissolved in DCM (10mL) in a 100-mL flask. Thionyl chloride (3.63 mL, 49.8 mmol) was addedslowly in several portions. The reaction was continued for overnight atambient temperature to completion. The reaction was work up withsaturated NaCl solution and extracted with DCM 50 (mL×3). The extractedDCM solution was dried over Na₂SO₄, filtrated, and concentrated underthe reduced pressure. The residue was solidified to give a product (2.64g, 80% yield) after high vacuo drying. ¹H NMR (500 MHz, CDCl₃) δ 2.94(4H, t, J=7.0 Hz), 3.52 (4H, t, J=7.0 Hz), 3.76 (2H, s), 7.28-7.36 (5H,m).

Preparation 2-(4-benzylpiperazin-1-yl)propan-1-ol: Thebis-(2-chloro-ethyl)-(4-benzyl)-amine (1.01 g, 4.35 mmol) was dissolvedin EtOH (40 mL) in a 250-mL flask. 2-Aminopropan-1-ol (347 mL, 4.35mmol) and triethylamine (1.27 mL, 9.14 mmol) were added and the reactionwas kept at 40° C. in an oil bath. After 24 hrs, the temperature wasincreased to 50° C. and the reaction was kept for another 24 hrs tocomplete. The reaction was quenched with saturated NH₄Cl solution andextracted with DCM (30 mL×3). The combined DCM solution was washed withNaCl saturated solution and dried over Na₂SO₄. After filtration, thesolution was concentrated under the reduced pressure. The residue waspurified by silica gel column to give a colorless product (252 mg, 25%yield) after the solvent was evaporated. The product solidified afterhigh vacuo. LC-MS (ESI, MH⁺) 235.4; ¹H NMR (500 MHz, CDCl₃) δ 0.92 (3H,d, J=6.5 Hz), 2.45-2.58 (6H, b), 2.67-2.8 (2H, m), 2.78-2.85 (1H, m),3.31 (1H, t, J=10.5 Hz), 3.42 (1H, dd, J=5.0, 10.5 Hz), 3.52 (2H, s),7.26-7.33 (5H, m).

Preparation of 2-(piperazin-1-yl)propan-1-ol: To a solution of2-(4-benzylpiperazin-1-yl)propan-1-ol (287 mg, 1.225 mmol) in methanol(10 mL) was added Pd(OH)₂/C (20% wt, 38 mg). The mixture was stirredvigorously under H₂ atmosphere for 15 h. LC-MS analysis indicated thestarting material was consumed completely. Solids were filtered off andfiltrate was concentrated on Rotavap under reduced pressure. Theresulting residue (173 mg) was used directly for next step reactionwithout further purification. LC-MS [ESI-MH⁺]: m/z 145. ¹H-NMR (500 MHz,CDCl₃) δ 1.212 (3H, d, J=6.5 Hz), 2.534 (2H, m), 2.840 (2H, m), 2.868(1H, m), 2.984 (2H, m), 3.047 (2H, m), 3.309 (1H, m), 3.430 (1H, m).

Preparation of2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol:2-(Piperazin-1-yl)propan-1-ol (171 mg, 1.185 mmol),3,6-dichloro-1,2,4-triazin-5-amine (170 mg, 1.03 mmol) and triethylamine(0.402 ml, 2.89 mmol) were dissolved in p-dioxane (5 mL). The solutionwas heated at 95° C. on microwave reactor for 3 h. Solids were filteredoff and filtrate was concentrated under reduced pressure. The resultingresidue was subject to flash column chromatography. Yield product asyellowish solids (200 mg, 64% yield). LC-MS [ESI-MH⁺]: m/z 273; ¹H-NMR(500 MHz, DMSO-d₆) δ 1.253 (3H, d, J=6.5 Hz), 3.143 (2H, m), 3.376 (2H,m), 3.483 (2H, m), 3.606 (1H, m), 3.751 (1H, m), 4.578 (2H, d, J=13.0Hz), 5.505 (1H, s), 7.480 (1H, br), 7.996 (1H, br).

Preparation of2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol:2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol (80mg, 0.293 mmol), 2,3-dichlorophenyl)boronic acid (84 mg, 0.44 mmol),cesium carbonate (191 mg, 0.587 mmol) were dissolved in 2 mL degassedp-dioxane/H₂O (v/v 3:1) and tetrakis(triphenylphosphine)palladium (85mg, 0.073 mmol) was added under nitrogen atmosphere. The reactionmixture was stirred at 85° C. for 3 hours. Solids were filtered off andfiltrate was concentrated under reduced pressure. The residue wassubject to flash column chromatography to give a product as yellow solid(52 mg, 96.5% purity, 45.0% yield). LC-MS [ESI-MH⁺]: m/z 383; ¹H-NMR(500 MHz, DMSO-d₆) δ 0.945 (3H, d, J=6.5 Hz), 2.550 (4H, m), 2.610 (1H,m), 3.702 (4H, br), 4.026 (1H, m), 4.340 (1H, dd, J₁=4.5 Hz, J₂=6.5 Hz).6.450-7.100 (1H, br), 7.358 (1H, dd, J₁=1.5 Hz, J₂=8.0 Hz), 7.448 (1H,t, J=2.5 Hz), 7.710 (1H, dd, J=1.5 Hz, J₂=8.0 Hz).

The product was dissolved in methanol and 4 equiv. HCl aqueous solutionwas added. Methanol was removed under reduced pressure. The remainingsolution was frozen and lyophilized for 2 days to afford hydrochloridesalt.

Example 38 Preparation of Compound 90 Preparation of2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methylpropan-1-ol(Compound 90)

Preparation of 2-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol: Thebis-(2-chloro-ethyl)-(4-benyl)-amine (1.83 g, 7.88 mmol) was dissolvedin EtOH (75 mL) in a 250-mL flask. 2-Amino-2-methylpropan-1-ol (752 mL,7.88 mmol) was added and the reaction was kept at 40° C. in an oil bathover 60 hrs. The reaction was quenched with saturated NH₄C solution andextracted with DCM (40 mL×3). The combined DCM solution was washed withNaCl saturated solution and dried over Na₂SO₄. After filtration, thesolution was concentrated under the reduced pressure. The residue waspurified on silica gel column to give a solidified product (503 mg, 26%yield) after evaporate the solvent and high vacuo drying. LC-MS (ESI,MH⁺) 249.3; ¹H NMR (500 MHz, CDCl₃) δ 1.03 (6H, s), 2.40-2.65 (8H, b),3.32 (2H, s), 3.50 (2H, s), 7.25-7.32 (5H, m).

Preparation of 2-methyl-2-(piperazin-1-yl)propan-1-ol: To a solution of2-(4-benzylpiperazin-1-yl)-2-methylpropan-1-ol (240 mg, 0.966 mmol) inmethanol (10 mL) was added Pd(OH)₂/C (20% wt, 27 mg). The mixture wasstirred vigorously under H₂ atmosphere for 15 h. LC-MS analysisindicated the starting material was consumed completely. Solids werefiltered off and filtrate was concentrated on Rotavap under reducedpressure. The resulting residue (140 mg) was used directly for next stepreaction without further purification. LC-MS [ESI-MH⁺]: m/z 159.

Preparation of2-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methyl-propan-1-ol:2-Methyl-2-(piperazin-1-yl)propan-1-ol (140 mg, 0.885 mmol),3,6-dichloro-1,2,4-triazin-5-amine (127 mg, 0.769 mmol) andtriethylamine (0.32 ml, 2.31 mmol) were dissolved in dioxane (5 mL). Thesolution was heated at 95° C. on microwave reactor for 3 h. Solids werefiltered off and filtrate was concentrated under reduced pressure. Theresulting residue was subject to flash column chromatography to give aproduct as yellowish solids (124 mg, 56.2% yield). LC-MS [ESI-MH⁺]: m/z287; ¹H-NMR (500 MHz, DMSO-d6) δ 0.943 (6H, s), 2.568 (4H, t, J=5.0 Hz),3.283 (2H, d, J=5.5 Hz), 3.595 (4H, t, J=5.0 Hz), 4.298 (1H, t, J=5.0Hz), 7.302 (1H, br), 7.766 (1H, br).

Preparation of2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methylpropan-1-ol:2-(4-(5-Amino-6-chloro-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methyl-propan-1-ol(120 mg, 0.418 mmol), (2,3-dichlorophenyl)boronic acid (120 mg, 0.628mmol), cesium carbonate (273 mg, 0.837 mmol) were dissolved in 2 mLdegassed p-dioxane/H₂O (v/v 3:1) andtetrakis(triphenylphosphine)palladium (121 mg, 0.105 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.for 3 hours. LC-MS analysis indicated the reaction was complete. Solidswere filtered off and filtrate was concentrated under reduced pressure.The residue was subject to flash column chromatography to give a productas white solid (60 mg, 95.5% purity, 32.0% yield). LC-MS [ESI-MH⁺]: m/z397; ¹H-NMR (500 MHz, DMSO-d6) δ 0.945 (6H, s), 2.550 (4H, m), 2.610(1H, m), 3.493 (1H, m), 3.702 (4H, br), 6.450-7.100 (1H, br), 7.358 (1H,dd, J₁=1.5 Hz, J₂=8.0 Hz), 7.448 (1H, t, J=2.5 Hz), 7.710 (1H, dd,J₁=1.5 Hz, J₂=8.0 Hz).

The product was dissolved in methanol and 4 equiv. HCl aqueous solutionwas added. Methanol was removed under reduced pressure. The remainingsolution was frozen and lyophilized for 2 days to afford hydrochloridesalt.

Example 39 Preparation of Compound 91 Preparation of(S)-1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol(Compound 91)

Preparation of (S)-1-amino-3-(2,2,2-trifluoroethoxy)propan-2-ol:(S)-2-((2,2,2-Trifluoroethoxy)methyl)oxirane (184 mg, 1.176 mmol) in THF(15 mL) was dropwise added to 7N ammonia in MeOH (1.7 ml, 11.8 mmol) in1 h by a syringe pump. Then the mixture was stirred at ambienttemperature for 2 days. Solvent was stripped off under reduced vacuum togive a liquid residue (184 mg, 90% yield). ¹H-NMR (500 MHz, CDCl₃) δ2.755 (1H, dd, J₁=7.5 Hz, J₂=17.5 Hz), 2.887 (1H, dd, J=4.0 Hz, J₂=13.0Hz), 3.626 (1H, m), 3.709 (1H, m), 3.762 (1H, m), 3.901 (2H, q, J₁=8.5Hz).

Preparation of(S)-1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol:(S)-1-Amino-3-(2,2,2-trifluoroethoxy)propan-2-ol (100 mg, 0.678 mmol),3,6-dichloro-1,2,4-triazin-5-amine (286 mg, 1.733 mmol) andtriethylamine (225 μL, 1.617 mmol) were dissolved in p-dioxane (5 mL).The solution was heated at 95° C. on microwave reactor for 3 h. Solidswere filtered off and filtrate was concentrated under reduced pressure.The resulting residue was subject to flash column chromatography to givea product as yellowish solids (67 mg, 38.5% yield). LC-MS [ESI-MH⁺]: m/z302; ¹H-NMR (500 MHz, CDCl₃) δ 3.502 (1H, m), 3.690 (oct, J₁=6.0 Hz,J₂=10.0 Hz, J₃=31.0 Hz), 3.906 (2H, q, J=9.0 Hz), 4.050 (1H, m), 5.513(2H, br).

Preparation of(S)-1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol:(S)-1-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol(67 mg, 0.222 mmol), (2,3-dichlorophenyl)boronic acid (85 mg, 0.444mmol), cesium carbonate (145 mg, 0.444 mmol) were dissolved in 2 mLdegassed p-dioxane/H₂O (v/v 3:1) andtetrakis(triphenylphosphine)palladium (121 mg, 0.105 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.for 3 hours. LC-MS analysis indicated the reaction was completed. Solidswere filtered off and filtrate was concentrated under reduced pressure.The residue was subject to flash column chromatography to give a productas white solids (70 mg, 95.3%, 76% yield). LC-MS [ESI-MH⁺]: m/z 412;¹H-NMR (500 MHz, CDCl₃) δ 3.641 (1H, br), 3.709 (3H, m), 3.923 (2H, q,J=8.0 Hz), 4.115 (1H, m), 5.3-6.2 (1H, br), 7.400 (2H, m), 7.650 (1H,m).

The product was dissolved in methanol and 4 equiv. HCl aqueous solutionwas added. Methanol was removed under reduced pressure. The remainingsolution was frozen and lyophilized for 2 days to afford hydrochloridesalt.

Example 40 Preparation of Compound 92 Preparation of3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propane-1,2-diol(Compound 92)

In a 50-mL flask,6-(2,3-dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (101 mg,0.311 mmol) was added in dioxane (1.5 mL). The oxirano-2-ylmethanol(0.206 mL, 3.11 mmol) and DMAP (7.61 mg, 0.062 mmol) were added. Thereaction was heated up to 110° C. in an oil bath for 3 hrs. The solutionwas evaporated and the residue was purified by silica gel column. Theproduct fractions were combined and solvent was evaporated to give anoil-like product (46.2 mg, 37% yield). RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 3.97 min (with purity 93.5%); LC-MS (ESI, MH⁺)400.2; ¹H NMR (500 MHz, CDCl₃) δ 2.41-2.45 (1H, m), 2.54-2.56 (2H, m),2.66 (1H, t, J=10.0 Hz), 2.75-2.78 (2H, m), 3.53-3.56 (1H, m), 3.76-3.82(1H, m), 3.89-3.97 (5H, bm), 4.80 (2H, s), 7.35-7.39 (2H, m), 9.58-7.60(1H, m).

The free base was dissolved in diluted HCl/MeOH (0.125 M) and stirredfor 15 min before it was evaporated. The dried HCl salt was thenre-dissolved in deionized water. After filtration, the clear watersolution was cool down to freeze, and lyophilization to give theoff-white solid product as hydrochloride salt.

Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)-sulfonyl)ethanol

Preparation ofN-3-(2-chloroethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine:In a 100-mL flask,2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-amino)ethanol(504 mg, 1.68 mmol) was dissolved in dioxane (35 mL). Thionyl chloride(367 mL, 5.04 mmol) was added following by TEA (0.773 mL, 5.55 mmol).The reaction was let it going overnight before it was quenched withNH₄Cl saturated solution and extracted with DCM 50 (mL×3). The extractedDCM solution was dried over Na₂SO₄, filtrated, and concentrated underthe reduced pressure. The residue solidified to give a product (475 mg,89% yield) after high vacuo drying. RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 5.50 min; LC-MS (ESI, MH⁺) 319.6; ¹H NMR (500MHz, CDCl₃) δ 1.33 (2H, d, J=6.5 Hz), 3.66-3.70 (2H, m), 7.45-7.48 (2H,m), 7.72-7.74 (2H, m).

Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)thio)ethanol:In a 100-mL flask,N-3-(2-chloroethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(80 mg, 0.250 mmol) was dissolved in BuOH (1.8 mL). 2-mercaptoethanol(140 μL, 2.0 mmol) was added together with KOtBu (2.0 mL, 1M). Thereaction mixture was heated up to 50° C. and completed in 40 min byLC-MS. The reaction was stopped by mixing with saturated NH₄Cl (80 mL)and extracted with DCM (30 mL×3). The combined DCM solution was driedover Na₂SO₄, filtrated, and concentrated under the pressure to give aproduct (32 mg, 36% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 5.15 min; LC-MS (ESI, MH⁺) 360.0; ¹H NMR (500 MHz, CDCl₃)δ 2.82-2.86 (2H, m), 2.89-2.92 (2H, t, J=6.0 Hz), 3.82 (2H, t, J=6.0Hz), 3.94 (2H, t, J=5.5 Hz), 7.37-7.39 (2H, m), 7.59-7.61 (1H, m).

Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)sulfonyl)ethanol:2-((2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)thio)ethanol(286 mg, 0.794 mmol) was dissolved in MeOH (5 mL) in 100-mL flask. Oxone(1.46 g, 2.38 mmol) was added and the reaction was kept at roomtemperature for overnight. The residue was dissolved in saturated NH₄Clsolution and extracted with DCM (20 mL×3). The combined DCM solution wasdried over Na₂SO₄ and after filtration, it was concentrated under thepressure. The residue was purified on a silica gel column to give aproduct (70 mg, 22.5% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 6.72 min; LC-MS (ESI, MH⁺) 392.0; ¹H NMR (500 MHz, D₂O) δ3.16 (1H, t, J=1.5 Hz), 3.21 (2H, t, J=9.5 Hz), 3.42 (2H, t, J=6.5 Hz),3.83-3.86 (4H, m), 7.28-7.34 (2H, m), 7.59-7.61 (1H, m).

Example 41 Preparation of Compound 93 Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)sulfonyl)ethanol(Compound 93)

Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propan-1-ol:5-Amino-3,6-dichloro-1,2,4-triazine (1.5 g, 9.09 mmol) was dissolved indioxane (60 mL) at room temperature. Triethylamine (1.9 mL, 13.6 mmol)was added, followed by addition of 2-aminopropan-1-ol (1.37 g, 18.2mmol). The resulting mixture was stirred at 95° C. for overnight. Afterovernight reaction, the mixture was cooled down to room temperature,filtered, and the organic solution was concentrated. The residue waspurified on silica gel column to afford a solid product (1.93 g). LC-MS(ESI, MH⁺) 413; HPLC: >85%

Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-1-ol:(2,3-dichlorophenyl) boronic acid (1.93 g, 10.1 mmol),2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propan-1-ol (1.37 g, 6.73mmol), cesium carbonate (4.38 g, 13.5 mmol) were dissolved in 150 mLdegassed mixture of dioxane/H₂O (3:1) and tetrakis(triphenylphosphine)palladium (1.49 g, 1.68 mmol) was added under nitrogen atmosphere. Thereaction mixture was stirred at 85° C. for 4 hours. Insoluble wasfiltered and solvent was evaporated to dryness at 50° C. The residue waspurified on silica gel column to afford a solid product (1.54 g, 73%yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.57min (with purity 97.4%); LC-MS (ESI, MH⁺) 314; ¹H NMR (500 MHz, CDCl₃) δ1.29-1.31 (2H, d), 3.49-3.68 (1H, m), 3.80-3.83 (1H, m), 4.17 (1H, bs),4.92 (2H, br), 7.36-7.38 (2H, m), 7.57-7.60 (1H, m).

Preparation ofN3-(1-chloropropan-2-yl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine:2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-1-ol(150 mg, 0.478 mmol) was dissolved in 15 mL of dioxane. Thionyl chloride(0.135 mL, 1.43 mmol) was added slowly and the reaction was stirred atroom temperature for 30 min. Triethylamine (0.20 mL, 1.57 mmol) wasadded. The reaction mixture was stirred at room temperature forovernight. Solvent was evaporated. Residue was dissolved in 60 mL ofdichloromethane and 5 mL of methanol, washed with saturated NH₄Cl (10ml×3). Dichloromethane solution was dried over anhydrous sodium sulfate,concentrated, and solvent was evaporated to dryness to afford 150 mg ofsolid product. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min)5.89 min (with purity 87.3%); LC-MS (ESI, MH⁺) 332.

Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)thio)ethanol:N3-(1-chloropropan-2-yl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(150 mg, 0.451 mmol)) was dissolved in 4 mL of 1.0 N potassiumtert-butoxide solution. 2-Mercaptoethanol (0.253 mL) was added. Thereaction mixture was heated at 50° C. for 2.5 hrs using microwavereactor. Reaction mixture was mixed with sat MH₄Cl (50 mL), wasextracted with dichloromethane (20 mL×3). Combined dichloromethane wasdried with anhydrous MgSO₄, filtered, and solvent was evaporated todryness. The residue was purified on silica gel to afford 30 mg productas solid. LC-MS (ESI, MH⁺) 374.

Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)sulfonyl)ethanol:2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)thio)ethanol(30 mg, 0.08 mmol) was dissolved in 5 mL of mixture methanol-deionizedwater. Oxone monopersulfate compound (73.9 mg, 0.24 mmol) was added. Themixture was stirred at room temperature for overnight. Solvent wasconcentrated. The residue was purified with on silica gel to affordproduct (14 mg). LC-MS (ESI, MH⁺) 406.

Preparation of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)sulfonyl)ethanol.HClSalt:2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)sulfonyl)ethanol(14 mg) was dissolved in 15 mL of 0.5N HCl aqueous. The aqueous wasdried by lyophlization to afford 15 mg of2-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propyl)sulfonyl)ethanolas hydrochloride salt. RP-HPLC (betasil C18, 0.5 mL/min, 1.0-100% ACN in10 min) 4.81 min (with purity 98.4%); LC-MS (ESI, MH⁺) 406; ¹H NMR (500MHz, D₂O) δ 1.42-1.44 (2H, d), 3.48-3.67 (4H, m), 3.80-3.89 (1H, m),4.03-4.10 (2H, m), 7.43-7.50 (2H, m), 7.76-7.78 (1H, dd).

Example 42 Preparation of Compound 94 Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94)

Preparation of(R)-benzyl-4-(3-chloro-2-hydroxypropyl)-piperazine-1-carboxylate:1-Z-Piperazine (2.21 mL, 11.44 mmol) was dissolved in EtOH (48 mL) atroom temperature in a 250-mL flask. (R)-epichlorohydrin (1.26 mL, 16.02mmol) was added. The reaction was kept at ambient temperature forovernight and then with elevated temperature at 50° C. for another 5hrs. The ethanol solution was evaporated and the residue was dissolvedin saturated NH₄Cl solution and extracted with DCM (50 mL×3). Thecombined DCM phase was washed with saturated NaCl solution before it wasdried over Na₂SO₄. After filtration, the solution was concentrated underthe reduced pressure. The residue was dried overnight to give anoil-like product (3.52 grams, 98% yield). No further purification wasapplied. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) ELSDsignal 4.52 min; LC-MS (ESI, MH⁺) 313.2; ¹H NMR (500 MHz, CDCl₃) δ 2.45(2H, bs), 2.53 (2H, d, J=7.0 Hz), 2.63 (2H, bs), 3.51-3.64 (6H, m),3.94-3.99 (1H, m), 5.15 (2H, s), 7.33-7.39 (5H, m).

Preparation of(R)-benzyl-4-(oxiran-2-ylmethyl)-piperazine-1-carboxylate: The aboveresidue (3.52 g, 11.25 mmol) was dissolved in THF (30 mL) in a 250-mLflask. A NaOH solution was prepared using 4.0 gram of solid NaOHdissolving in water (50 mL). After cool down to room temperature, thisbasic solution was added to the above THF solution with vigorouslystirring. LC-MS indicated the reaction was completed in 20 min. Theabove basic solution was then diluted with NH₄Cl saturated solution (150mL) and extracted with DCM (50 mL×3). The combined DCM phase was washedwith saturated NaCl solution (80 mL) and carefully dried over Na₂SO₄.After filtration, the solution was concentrated under the reducedpressure. The residue was set up for high vacuo for overnight and gave2.73 grams (88%) of epoxide product. No further purification wasapplied. RP-HPLC (betasil C18, 0.5 mL/min, 1.0-100% ACN in 10 min) ELSDsignal 4.14 min; LC-MS (ESI, MH⁺) 277.2; ¹H NMR (500 MHz, CDCl₃) δ 2.28(1H, dd, J=13.0, 7.0 Hz), 2.49 (2H, bs), 2.51 (1H, dd, J=5.0, 3.0 Hz),2.57-2.62 (2H, m), 2.78-2.82 (2H, m), 3.10-3.13 (1H, m), 3.57 (4H, 6s),5.15 (2H, s), 7.33-7.40 (5H, m).

Preparation of(R)-benzyl-4-(2-hydroxy-3-(2,2,2-trifluoroethoxy)-propyl)-piperazine-carboxylate:The above epoxide product (2.29 g, 8.27 mmol) was dissolved in DMF (42mL) in a 250-mL flask. Trifluoroethanol (1.89 mL, 24.8 mmol) and cesiumcarbonate (1.62 g, 4.96 mmol) were added. The reaction was set up at100° C. for the 1^(st) hours and more trifluoroethanol (630 μL) wasadded before the temperature was increased to 110° C. for 3 hrs. Aftercool down, the solution was quenched with saturated NH₄Cl (150 mL) andextraction with DCM (50 mL×3). The combined DCM phase was washed withsaturated NaCl solution (80 mL) before it was dried over Na₂SO₄. Afterfiltration, the solution was concentration under the reduced pressure.The DMF solvent was evaporated and the residue was further dried underhigh vacuo for overnight. The residue was then re-dissolved in DCM andpurified on silica gel column. After high vacuo for overnight, anoil-like product (2.44 g, 78% yield) was obtained. -HPLC (betasil C18,0.5 mL/min, 10-100% ACN in 10 min) ELSD signal 5.78 min; LC-MS (ESI,MH⁺) 377.2; ¹H NMR (500 MHz, CDCl₃) δ 2.42 (1H, dd, J=12.5, 4.0 Hz),2.43 (2H, bs), 2.52 (1H, dd, J=12.5, 10.0 Hz), 2.63 (2H, bs), 3.51-3.55(4H, m), 3.63 (11H, dd, J=10.0, 5.0 Hz), 3.72 (1H, dd, J=5.0, 3.5 Hz),3.90-3.97 (3H, m), 5.15 (2H, s), 7.34-7.39 (5H, m).

Preparation of(R)-1-(piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol-HAc: Theabove Cbz-protected product (2.44 g, 6.48 mmol) was dissolved in ethanol(65 mL) in a 250-mL flask. Acetic acid (742 μL, 12.97 mmol) was added.The flask was purged with N₂ once before Pd(OH)₂ catalysis (244 mg, 20%wt) was added. A H₂ balloon was prepared with a three way joint. Thereaction system was exchanged with H₂ twice before the reaction startedwith vigorously stirring. The deprotection completed in 30 min withgravity filtration and the catalyst residue was washed with MeOH 3times. The combined alcohol solution was evaporated under reducedpressure and an oil-like product 2.2 gram (quantitative yield) wasobtained after overnight high vacuo drying. RP-HPLC (betasil C18, 0.5mL/min, 10-100% ACN in 10 min) ELSD signal 1.26 min; LC-MS (ESI, MH⁺)not available; ¹H NMR (500 MHz, D₂O) δ 1.89 (3H, s, HAc), 2.57 (2H, d,J=6.0 Hz), 2.80-2.83 (4H, 6 m), 3.25 (4H, t, J=5.0 Hz), 3.63 (1H, dd,J=10.5, 6.0 Hz)), 3.73 (1H, dd, J=10.5, 3.5 Hz), 4.03 (2H, q, J=9.0 Hz),4.04 (1H, m).

Preparation of(R)-1-(4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)propan-2-ol:The above HAc salt product was dissolved in dioxane (7 mL) in a 100-mLflask. 3,6-dichloro-1,2,4-triazine-5-amine (324 mg, 1.96 mmol) and TEA(684 μL, 4.91 mmol) were added to the reaction solution. The reactionwas set up at 85° C. and LC-MS indicated the completeness of reaction intwo hours. The reaction residue was evaporated and overnight high vacuodrying before next step reaction. RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 5.78 min; LC-MS (ESI, MH⁺) 377.2; ¹H NMR (500MHz, CDCl₃) δ 2.42 (1H, dd, J=12.5, 4.0 Hz), 2.43 (2H, bs), 2.52 (1H,dd, J=12.5, 10.0 Hz), 2.63 (2H, bs), 3.51-3.55 (4H, m), 3.63 (1H, dd,J=10.0, 5.0 Hz), 3.72 (1H, dd, J=5.0, 3.5 Hz), 3.90-3.97 (3H, m), 5.15(2H, s), 7.34-7.39 (5H, m).

Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol:The above residue (1.55 g, 4.18 mmol) was suspended in a mixturesolution of dioxane (65 mL) and water (15 mL) in the original 250-mLflask. (2,3-Dichlorophenyl)-boronic acid (997 mg, 5.23 mmol) and cesiumcarbonate (2.48 g, 7.53 mmol) were added to the reaction solution. Afterpurged with N₂ once, the tetrakis(triphenylphosphine)palladium catalyst(966 mg, 0.836 mmol) was added with another 2 min vacuo bubbling beforethe reaction was started warm up to 85° C. in oil bath. Reaction in 3hrs before the solution was evaporated under reduce pressure and theresidue was then dissolved in methanol and azotropic evaporation 3 timesuntil it looks dry. High vacuo drying the residue overnight before itwas dissolved in methanol 5 mL and filtration. The residue was washedwith methanol (3 mL×2). The solution was evaporated and the residue waspurified on silica gel column. The product fractions were combined andthe solvent was evaporated and high vacuo gives the off-white product869 mg (43.2% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in10 min) 4.82 min (with purity 98.2%); LC-MS (ESI, MH⁺) 481.0; ¹H NMR(500 MHz, CDCl₃) δ 2.45 (1H, dd, J=12.0, 3.0 Hz), 2.52-2.58 (3H, m),2.72-2.74 (2H, m), 3.64 (1H, dd, J=10.0, 5.0 Hz), 3.73 (1H, dd, J=10.0,3.5 Hz), 3.91-3.97 (7H, m), 4.86 (2H, bs), 7.34-7.38 (2H, m), 7.56-7.58(1H, m). The chiral column: CHIRALCEL OD-H (Lot No. ODH0CD-SA010);Column Size: 0.46 cm (I.D)×15 cm (L); Mobile Phase:n-Hexane/Ethanol=90/10 (v/v); Flow rate: 1.0 mL/min; Injection: 10 μL;Detection: UV 220 nm; Column Temp: 35° C.; Program: Isocratic. Theproduct enantiomeric purity 89.1% ee.

Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol.2HCl:The above purified product (1.56 g, 3.24 mmol) was dissolved in methanol(30 mL) in a 500-mL flask. The HCl/methanol (1.25M, 13 mL, 16.2 mmol)was diluted with methanol (100 mL) and was added to the above solution.After stirring for 5 min, the methanol was slowly evaporated under thereduce pressure. The residue was high vacuo dried before it wasredissolved in deionized water (160 mL). The cloudy solution was vacuofiltrated before it was freeze. It was then lyophilized over 5 daysbefore the off-white solid product (1.67 g, 93% yield) was obtained.RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.83 min; LC-MS(ESI, MH⁺) 481.0; ¹H NMR (500 MHz, CDCl₃) δ 3.21-3.26 (2H, m), 3.0-3.8(6H, bs), 3.62 (1H, dd, J=10.5, 5.0 Hz), 3.68 (1H, dd, J=10.5, 4.5 Hz),3.90-3.98 (3H, m), 4.21-4.25 (2H, m), 7.30 (1H, d, J=7.5 Hz), 7.35 (1H,t, J=7.5 Hz), 7.62 (1H, d, J=8.0 Hz).

The S-form HCl salt product (Compound 95) was prepared using a similarstrategy. The spectra of the product is identical to the R-form product.

Example 43 Preparation of Compound 96 Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96)

Preparation of(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol:Piperazine-lamotrigine (100 mg), (R)-(−)-Glycidyl methyl ether (54 mg)were dissolved in 1.5 mL of methanol. The reaction was carried onmicrowave reactor at 90° C. for 60 minutes. A sample was checked byLC-MS and showed the reaction was completed. The reaction mixture wasconcentrated and purified on silica gel column. Fractions were combinedto give product (75 mg) after overnight vacuo. LC-MS (ESI, MH⁺) 413;HPLC: >97%

The above product was dissolved in 10 mL methanol, 0.8 mL of 1.25M HClin methanol was added. The mixture was stirred at ambient temperaturefor 10 min. Solvent was evaporated to dryness; the residue was dissolvedin 10 mL of deionized water. The solution was filtrated before it wasfreeze and lyophilized for two days to give the final hydrochloridesalts: 80 mg. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min)4.33 min (with purity 97.4%); LC-MS (ESI, MH⁺, free base) 413; ¹H NMR(500 MHz, D₂O) δ 3.34-3.36 (2H, m), 3.38 (3H, s), 3.40-3.59 (8H, m, bs),4.29-4.33 (1H, m), 7.43-7.51 (2H, m), 7.76-7.78 (1H, dd).

Example 44 Preparation of Compound 97 Preparation of(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97)

Preparation of(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol

Piperazine-lamotrigine (1.3 g), (R)-(−)-Glycidyl methyl ether (704 mg)were dissolved in 15 mL of methanol. The reaction was carried onmicrowave reactor at 90° C. for 60 minutes. A sample was checked byLC-MS and showed the reaction was completed. The reaction mixture wasconcentrated and purified on silica gel column to obtain 694 mg ofproduct. LC-MS (ESI, MH⁺) 413; HPLC: >95%

The above product was dissolved in 70 mL methanol, 6.7 mL of 1.25M HClin methanol was added. The mixture was stirred at ambient temperaturefor 10 min. Solvent was evaporated to dryness, residue was dissolved in20 mL of deionized water. The solution was filtrated before it wasfreeze and was lyophilized for two days to give the final hydrochloridesalts: 725 mg. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min)4.27 min (with purity 95.9%); LC-MS (ESI, MH⁺) 413; ¹H NMR (500 MHz,D₂O) δ 3.34-3.36 (2H, m), 3.38 (3H, s), 3.40-3.59 (8H, m), 4.29-4.33(1H, m), 7.43-7.51 (2H, m), 7.76-7.78 (1H, dd).

Example 45 Preparation of Compound 98 Preparation of(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98)

Preparation of(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol:Piperazine-lamotrigine (750 mg, Compound 79),(S)-(−)-3,3,3-Trifluoro-1,2-epoxypropane (465 mg) were dissolved in 10mL of methanol. The reaction was carried on microwave reactor at 95° C.for 45 minutes. A sample was checked by LC-MS and showed the reactionwas completed. The reaction mixture was concentrated and purified onsilica gel column to give 667 mg of product. LC-MS (ESI, MH⁺) 437; ¹HNMR (500 MHz, CDCl₃) δ 2.73-2.85 (6H, m), 4.01 (4H, bs), 4.22 (1H, bs),4.76 (2H, m), 7.34-7.36 (2H, m), 7.56-7.59 (1H, m).

The above product (667 mg) was dissolved in 60 mL methanol, 6.1 mL of1.25M HCl in methanol was added. The mixture was stirred at ambienttemperature for 10 min.

Solvent was evaporated to dryness, residue was dissolved in 34 mL ofdeionized water (about 20% wt). The solution was filtrated before it wasfreeze and was lyophilized for two days to give the final HCl salts: 719mg. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.60 min(with purity 95.8%); LC-MS (ESI, MH⁺, free base) 437; ¹H NMR (500 MHz,D₂O) δ 3.50-3.62 (6H, m), 4.13 (4H, bs), 4.72-4.7 (1H, m), 7.43-7.51(2H, m), 7.76-7.78 (1H, m).

Example 46 Preparation of Compound 99 Preparation of6-(2,3-dichlorophenyl)-3-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)-1,2,4-triazin-5-amine.HClsalt (Compound 99)

Preparation of 1-benzylazetidin-3-yl methanesulfonate:1-Benzylazetidin-3-ol (1.0 g, 6.13 mmol) and triethylamine (1.7 mL,12.25 mmol) were dissolved in 100 ml of DCM. Methanesulfonyl chloride(0.50 ml, 6.43 mmol) was added, the mixture was stirred at roomtemperature for overnight. After overnight reaction, the mixture waswashed with 15 mL of saturated NH₄Cl aqueous solution, dried with MgSO₄,filtered, and solvent was evaporated to dryness to afford product (1.47g). LC-MS (ESI, MH⁺) 242; ¹H NMR (500 MHz, CDCl₃) δ 3.01 (3H, s),3.23-3.27 (2H, dd), 3.67 (2H, s), 3.66-3.74 (2H, dd), 5.07-5.12 (1H, m),7.25-7.34 (5H, m).

Preparation of 1-benzyl-3-(2,2,2-trifluoroethoxy)azetidine:2,2,2-Trifluoroethanol (3.06 g, 30.6 mmol) was dissolved in 50 mL ofdioxane. NaH (0.735 mg, 18.4 mmol) was added to the2,2,2-trifluoroethanol solution and stirred for 30 minutes. To themixture of 2,2,2-trifluoroethanol and NaH, 1-benzylazetidin-3-ylmethanesulfonate (1.47 g, 6.12 mmol) was added and stirred at 80° C.under nitrogen atmosphere for 4 hours. After cooling to roomtemperature, insoluble was filtered and solvent was evaporated todryness at 50° C. The residue was purified on silica gel column toafford 0.82 g product as liquid in 56% yield. LC-MS (ESI, MH⁺) 246; ¹HNMR (500 MHz, CDCl3) δ 3.07 (2H, s), 3.69 (4H, br), 3.37-3.83 (2H, q),4.27-4.33 (1H, m), 7.28-7.44 (5H, m)

Preparation of 3-(2,2,2-trifluoroethoxy)azetidine:1-Benzyl-3-(2,2,2-trifluoro-ethoxy)azetidine (620 mg) was dissolved in62 mL of ethanol, Pt(OH)₂ (62 mg) and acetic acid (0.15 mL) were addedto ethanol solution. The mixture was hydrogenated using hydrogen balloonfor 2 days. After filtration, solvent was evaporated to dryness and theresidue was dried in vacuum to obtain product (395 mg) as liquid. Whilethe LC-MS showed that 1-benzyl-3-(2,2,2-trifluoroethoxy)azetidine wasnot detected, the product will be used directly for next reaction.

Preparation of6-chloro-3-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)-1,2,4-triazin-5-amine:A vial was charged with 3,6-dichloro-1,2,4-triazin-5-amine (1.35 mg,0.81.6 mmol) and triethylamine (0.34 mL, 2.45 mmol),3-(2,2,2-trifluoroethoxy)azetidine in 4 mL of dioxane. The mixture washeated at 95° C. for 3 hours using microwave reactor. Solvent wasevaporated to dryness, residue was used for next step reaction withoutpurification. LC-MS (ESI, MH⁺) 284

Preparation of6-(2,3-dichlorophenyl)-3-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)-1,2,4-triazin-5-amine-HCl.salt:(2,3-dichlorophenyl) boronic acid (234 mg, 1.24 mmol),6-chloro-3-(3-(2,2,2-trifluoroethoxy)azetidin-1-yl)-1,2,4-triazin-5-amine(231 mg, 0.82 mmol), cesium carbonate (532 mg, 1.63 mmol) were dissolvedin 20 mL degassed mixture of dioxane/H₂O (3:1) and tetrakis(triphenylphosphine)palladium (236 mg, 0.21 mmol) was added undernitrogen atmosphere. The reaction mixture was stirred at 85° C. for onehour. Insoluble was filtered and solvent was evaporated to dryness at50° C. The residue was purified on silica gel to afford product (204 mg)as solid. The product was further purified by dissolving in 30 mL of 0.5N HCl aqueous and 10 mL of dichloromethane, after separation, aqueouswas washed with dichloromethane (10 ml×2), then HCl aqueous waslyophilized for overnight to afford product (120 mg) as hydrochloridesalt. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 6.24 min(with purity 99.3%); LC-MS (ESI, MH⁺) 394; ¹H NMR (500 MHz, D₂O) δ3.98-4.04 (2H, q), 4.14-4.18 (2H, dd), 4.45-4.49 (2H, dd), 4.67-4.68(1H, m), 7.33-7.40 (2H, m), 7.66-7.68 (1H, dd).

Example 47 Preparation of Compound 100 Synthesis of3-N-mPEG₃-lamotrigine-d₃ (Compound 100)

Synthesis of 5-amino-3,6-dichloro-1,2,4-triazine

3,5,6-Trichloro-1,2,4-triazine (4.6114 g, 24.28 mmol) was dissolved inTHF (100 mL) at room temperature. And then triethylamine (5.0 mL, 35.9mmol) was added. The mixture was cooled to 0° C., ammonia in dioxane(0.5 M, 51 mL, 25.5 mmol) was added. The mixture was stirred at 0° C.for 30 min, at room temperature for 5 h. The mixture was filtered toremove the solid. The solid was washed with ethyl acetate. The combinedorganic solution was concentrated. The crude mixture was mixed withabout 50 mL of ethyl acetate and warmed up, and then cooled to roomtemperature. The solid was collected and washed with ether to afford thefirst partial product. The solution was concentrated to remove all ofsolvents. The residue was mixed with about 5 ml of ethyl acetate, thesolid was collected and dried. The solution was purified with flashcolumn chromatography on silica gel using 35-100% ethyl acetate/hexanesto afford 3rd part of solid. The total of product was 3.8998 g and theyield was 97%. LC-MS: 165.1 (MH⁺/z).

Synthesis of2-(2,3-dichloro-phenyl-4,5,6-d₃)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1,2-dichloro-3-bromobenzene-d₃ (0.3535 g, 1.53 mmol),bis(pinacolato)diboron (0.590 g, 2.30 mmol), and potassium acetate(0.4649 g, 4.74 mmol) in anhydrous DMSO (14 mL) was stirred at roomtemperature. And then 1,1′-[bis(bisphenylphosphino)ferrocene]dichloropalladium (II) (0.057 g, 0.078 mmol) was added. Themixture was degassed with nitrogen, stirred at 95° C. for 3 h. Themixture was cooled to room temperature and added into water (150 mL).The mixture was extracted with ethyl acetate (3×50 mL). The combinedorganic solution was washed with saturated sodium chloride solution (100mL), dried over anhydrous sodium sulfate, and concentrated. The crudematerial was purified with flash column chromatography on silica gelwith 1-10% ethyl acetate/hexane to afford 0.241 g of product as solidwith slight green color in 57% yield.

Synthesis of 5-amino-6-chloro-3-mPEG₃-amino-1,2,4-triazine

5-Amino-3,5-dichloro-1,2,4-triazine (1.460 g, 8.85 mmol) was dissolvedin dioxane (30 mL) at room temperature. Triethylamine (2.7 mL, 19.37mmol) was added, followed by addition of mPEG₃-NH₂ (1.9812 g, 12.14mmol). The resulting mixture was stirred at 95° C. for 7 h. The mixturewas cooled to room temperature, filtered to remove the white solid andthe solid was washed with ethyl acetate. The combined organic solutionwas concentrated and purified with flash column chromatography on silicagel (1-10% methanol/dichloromethane) to afford 2.1236 g of product assolid. The yield was 82%.

¹H-NMR (500 MHz, CDCl₃): 3.691-3.654 (m, 6H, 3CH₂), 3.625-3.594 (m, 6H,3CH₂), 3.436 (s, 3H, CH₃). LC-MS: 292.1 (MH⁺/z).

Synthesis of 3-N-mPEG₃-lamotrigine-d₃: A mixture of2-(2,3-dichloro-phenyl-4,5,6-d₃)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(241 mg, 0.87 mmol), 5-amino-6-chloro-3-mPEG₃-amino-1,2,4-triazine(0.2527 g, 0.87 mmol), cesium carbonate (0.630 g, 1.91 mmol) andtetrakis(triphenylphosphine)palladium (54.1 mg, 0.047 mmol) indioxane/water (9 mL/3 mL) was purged with nitrogen and then heated at95° C. for 22 h. The mixture was concentrated under reduced pressure toremove the organic solvent. The residue was mixed with brine, extractedwith dichloromethane (2×100 mL). The combined organic solution waswashed with brine, dried over anhydrous sodium sulfate, concentrated.The crude mixture was purified with column chromatography on silica gelusing 1-10% methanol/ethyl acetate to afford 138.8 mg of product. Theyield was 43%. ¹H-NMR (500 MHz, DMSO-d₆): 6.90 (br, 3H), 3.56-3.50 (m,8H, 4CH₂), 3.46-3.43 (m, 4H, 2CH₂), 3.24 (s, 3H, CH₃). LC-MS: 405.2(MH⁺/z).

Example 48 Preparation of Compound 101 Synthesis of 5-hydroxylamotrigine (Compound 101)

Synthesis of 1-bromo-2.3-dichloro-5-methoxybenzene

1-Bromo-2,3-dichloro-5-fluorobenzene (1.0401 g, 4.27 mmol) was dissolvedin toluene (30 mL), and then the solvent was removed under reducedpressure. The residue was dried under high vacuum for a few minutes.Anhydrous THF (15 mL) was added to dissolve the starting material. Andthen sodium methanoxide (0.9873 g, 17.36 mmol) was added. The mixturewas heated at 75° C. for 4.5 h, cooled to room temperature. The mixturewas quenched with saturated ammonium chloride solution, concentrated toremove THF. The remaining mixture was extracted with ethyl acetate(4×150 mL). The organic solution was washed with brine, dried overanhydrous sodium sulfate, concentrated to dryness to afford 1.0188 g ofproduct as white solid in 93% yield. ¹H-NMR (500 MHz, CDCl₃): 7.109 (d,J=3.0 Hz, 1H), 6.988 (d, J=3.0 Hz, 1H), 3.786 (s, 3H).

Synthesis of2-(2,3-dichloro-5-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-2,3-dichloro-5-methoxybenzene (9.3601 g, 36.6mmol), bis (pinacolato)diboron (13.3339 g, 52.0 mmol), potassium acetate(10.7268 g, 109 mmol) and1,1′-[bis(bisphenylphosphino)ferrocene]dichloropalladium (II) (1.32 g,1.804 mmol) in anhydrous DMSO (100 mL) was stirred at 95° C. for 5.5 h.The mixture was cooled to room temperature and poured into ice. Themixture was extracted with ethyl acetate (3×200 mL). The combinedorganic solution was washed with saturated sodium chloride solution(3×150 mL), dried over anhydrous sodium sulfate, and concentrated. Theresidue was purified with flash column chromatography on silica gel byusing ethyl acetate/hexane to afford 9.6970 g of product in 88% yield.¹H-NMR (500 MHz, CDCl₃): 7.092 (d, J=3.0 Hz, 1H), 7.050 (d, J=3.0 Hz,1H), 3.794 (s, 3H), 1.368 (s, 9H).

Synthesis of 5-hydroxy lamotrigine: 5-Methoxy-lamotrigine (80.6 mg,0.282 mmol) was mixed with anhydrous dichloromethane (15 mL) at roomtemperature, and then 0.85 mL of boron tribromide solution 1.0 M indichloromethane (0.85 mmol) was added. The resulting mixture was stirredat room temperature for 1.5 h. More of boron tribromide solution (0.7mL) was added. The mixture was stirred at room temperature for 19 h.More of boron tribromide solution (2.4 mL) was added. The mixture wasstirred at room temperature for 4 h. More of boron tribromide solution(1.0 mL) was added. The mixture was stirred for 20 h. The mixture wasquenched with methanol. The mixture was concentrated to remove all oforganic solvents. The remaining mixture was extracted withdichloromethane (3×30 mL). The aqueous solution was collected andlyophilized. The residue was stirred in ammonia (˜3 mL) for 18 h. A fewdrops of methanol were added. The mixture was stirred for 15 min. Themixture was concentrated to remove all of solvents. The material waspurified with flash column chromatography on silica gel using 1-30%methanol/dichloro methane. The fractions were collected andconcentrated. About 25 mg of material was obtained. The material wasdissolved in ˜5 mL of THF, ethylenediamine (0.85 mL, 12.74 mmol) wasadded. A white suspension was obtained. The mixture was stirred at roomtemperature for 3 h, concentrated to remove all of solvents. Thematerial was purified with flash column chromatography on silica gelusing 1-30% methanol/dichloromethane. The fractions were collected andconcentrated to afford 20.8 mg of product as white solid. ¹H-NMR (500MHz, DMSO-d₆): 10.231 (s, 1H), 7.048 (s, 1H), 6.714 (s, 1H), 6.397 (s,2H). LC-MS: 272.0 (MH⁺/z).

Example 49 Preparation of Compound 102 Synthesis of3-N-piperazinyl-5′-O-mPEG₃-lamotrigine (Compound 102)

Synthesis of 3-N-piperazinyl-5′-O-mPEG₃-lamotrigine:3-N-(4-Boc-piperazinyl)-5′-O-mPEG₃-lamotrigine (112.6 mg) dissolved indichloromethane (5 mL), trifluoroacetic acid (3 mL) was added. Themixture was stirred at room temperature for 5.5 h. The mixture wasdiluted with dichloromethane, washed with saturated potassium carbonate,brine, dried over anhydrous sodium sulfate, concentrated. The residuewas purified with NH-column using 0-10% methanol/dichloromethane assolvents to afford product (75 mg). ¹H NMR (500 MHz, Chloroform-d) δ7.138 (d, J=3.0 Hz, 1H, Ar—H), 6.920 (d, J=3.0 Hz, 1H, Ar—H), 5.279 (br,2H, NH₂), 4.111 (t, J=4.5 Hz, 2H, CH₂), 3.853 (br, 4H, 2 CH₂), 3.817 (t,J=5.0 Hz, 2H, CH₂), 3.698-3.680 (m, 2H, 2CH₂), 3.648-3.603 (m, 4H,2CH₂), 3.526-3.507 (m, 2H, CH₂), 3.352 (s, 3H, CH₃), 2.946 (t, 4H, J=5.0Hz, 2CH₂). LC-MS: 487.0 (MH⁺/z).

Preparation of reactants was carried out as follows.

Synthesis of5-amino-6-chloro-3-N-(4-N-Boc-piperazinyl)amino-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (466 mg,2.82 mmol) and triethylamine (1.0 mL, 7.17 mmol), t-Boc-piperazine(0.5675 g, 2.96 mmol) in dioxane. The mixture was heated at 95° C. for1.5 h using microwave. The mixture was cooled to room temperature,filtered and the white solid was washed with ethyl acetate. The organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford 872.4 mg product as solid in 98% yield. ¹H NMR (500 MHz,Chloroform-d) δ 5.38 (br, 2H), 3.76-3.68 (m, 4H), 3.44 (dd, J=6.3, 3.9Hz, 4H), 1.42 (s, 9H). LC-MS: 315.0 (MH⁺/z).

Synthesis of 1-bromo-5-O-mPEG₃-2,3-dichlorobenzene

1-Bromo-2,3-dichloro-5-fluorobenzene (1.4618 g, 5.99 mmol) and mPEG₃-OH(1.1097 g, 6.76 mmol) was mixed with toluene (25 mL) and removed thesolvent. The remaining material was dried under high vacuum for a fewminutes. The mixture was dissolved in anhydrous THF (20 mL). 60% Sodiumhydride (0.3549 g, 8.87 mmol) was added. The resulting mixture washeated at 75° C. for 3 h. The mixture was cooled to room temperature.Saturated ammonium chloride aqueous solution was added to quench thereaction. The mixture was concentrated to remove the organic solvent.The remaining mixture was extracted with dichloromethane (3×20 mL). Thecombined organic solution was washed with brine, dried over anhydroussodium sulfate, concentrated. The residue was purified with biotageflash column using 15-100% ethyl acetate/hexane to afford the product(2.057 g, yield: 88%). ¹H NMR (500 MHz, Chloroform-d) δ 7.17 (d, J=2.9Hz, 1H), 7.05 (d, J=2.8 Hz, 1H), 4.16-4.07 (m, 2H), 3.89-3.83 (m, 2H),3.77-3.65 (m, 6H), 3.60-3.55 (m, 2H), 3.41 (s, 3H).

Synthesis of2-(2,3-dichloro-5-O-mPEG₃-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-2,3-dichloro-5-O-mPEG₃-benzene (1.7749 g, 4.57mmol), bis(pinacolato)diboron (1.7712 g, 6.91 mmol), potassium acetate(1.420 g, 14.47 mmol) and1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.1737 g,0.24 mmol) in anhydrous DMSO (30 mL) was degassed with nitrogen, stirredat 95° C. for 5 h. The mixture was cooled to room temperature and pouredinto ice. The mixture was extracted with ethyl acetate (3×50 mL). Thecombined organic solution was washed with saturated sodium chloridesolution (50 mL), dried over anhydrous sodium sulfate, and concentrated.The residue was separated with flash column chromatography on silica gelusing ethyl acetate/hexane to afford product (1.8639 g, yield: 94%). ¹HNMR (500 MHz, Chloroform-d) δ 7.103 (d, J=3.0 Hz, 1H), 7.06 (d, J=3.0Hz, 1H), 4.14-4.05 (m, 2H), 3.82 (m, 2H), 3.73-3.69 (m, 2H), 3.66-3.62(m, 4H), 3.54-3.52 (m, 2H), 3.36 (s, 3H), 1.34 (s, 9H).

Synthesis of 3-N-(4-Boc-piperazinyl)-5-O-mPEG₃-lamotrigine

A mixture of2-(2,3-dichloro-5-O-mPEG₃-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(664.8 g, 1.53 mmol), the3-(N-Boc-piperazinyl)amino-5-amino-6-chloro-1,2,4-triazine (287.9 mg,0.92 mmol) was dissolved in dioxane (10 mL). A solution of cesiumcarbonate (83 mg, 2.53 mmol) in water (2 mL) was added. And thentetrakis(triphenylphosphine)palladium (56.3 mg, 0.053 mmol) was added.The mixture was purged with nitrogen for a few minutes. The mixture washeated at 85° C. for 4 h 15 min using microwave. The mixture wasconcentrated under reduced pressure to dryness. The residue was mixedwith water, extracted with dichloromethane (4×20 mL). The organicsolution was concentrated. The residue was purified with flash columnchromatography to afford the product (178.2 mg, yield: 33%). ¹H NMR (500MHz, Chloroform-d) δ 7.14 (d, J=2.9 Hz, 1H), 6.91 (d, J=2.9 Hz, 1H),4.82 (br, 2H), 4.11 (dd, J=5.7, 3.6 Hz, 2H), 3.84-3.80 (m, 6H),3.71-3.58 (m, 6H), 3.51 (q, J=5.2 Hz, 6H), 3.35 (s, 3H), 1.47 (s, 9H).LC-MS: 315.0 (MH⁺/z).

Example 50 Preparation of Compound 103 Synthesis of3-N-(4′-N-mPEG₃-piperazinyl) lamotrigine (Compound 103) Synthesis ofN-mPEG₃-piperazine

A solution of potassium carbonate (2.2957 g, 16.61 mmol) in water (3 mL)was added to a mixture of t-Boc-piperazine (0.9837 g, 5.12 mmol) andmPEG₃-Br (1.3123 g, 5.78 mmol) in a vial. The resulting mixture washeated at 120° C. for 1.5 h by using microwave. The mixture was dilutedwith water, extracted with dichloromethane (3×30 mL). The combinedorganic solution was washed with brine, dried over brine, concentrated.The residue was dried under high vacuum to afford1-N-t-Boc-4-N-mPEG₃-piperazine. ¹H NMR (500 MHz, Chloroform-d) δ3.64-3.58 (m, 8H), 3.53-3.51 (m, 2H), 3.41 (m, 4H), 3.34 (s, 3H), 2.57(t, J=5.8 Hz, 2H), 2.43-2.41 (m, 4H), 1.44 (s, 9H).

1-N-t-Boc-4-N-mPEG₃-piperazine was dissolved in dichloromethane (10 mL),and trifluoroacetic acid (6 mL) was added. The mixture was stirred atroom temperature for 23 h. The mixture was concentrated to remove all ofsolvents. The residue was dried under high vacuum. The residue wasdissolved in dichloromethane, washed with saturated aqueous potassiumcarbonate, dried over anhydrous sodium sulfate, concentrated. Only 209mg of product was isolated. Sodium chloride was added to the aqueoussolution to saturate the mixture, and then extracted withdichloromethane again. The combined organic solution was dried overanhydrous sodium sulfate, concentrated to afford product (1.1578 g,yield: 97%). ¹H NMR (500 MHz, Chloroform-d) δ 3.60-3.55 (m, 8H),3.51-3.49 (m, 2H), 3.33 (s, 3H), 2.84 (t, J=4.8 Hz, 6-1), 2.53 (t, J=6.0Hz, 23H), 2.42 (br, 4H).

Synthesis of5-amino-6-chloro-3-(4′-N-mPEG₄-piperazinyl)amino-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (658.8 mg,3.99 mmol) and triethylamine (2.5 mL, 17.94 mmol), N-mPEG₃-piperazine(0.9471 g, 4.08 mmol) in dioxane (7.5 mL). The mixture was heated at 95°C. for 1.5 h using microwave. The mixture was cooled to roomtemperature, filtered and the white solid was washed withdichloromethane. The organic solution was concentrated. The residue waspurified with flash column chromatography on silica gel using 1-10%methanol/dichloromethane to afford product (1.2111 g, Yield: 84%). ¹HNMR (500 MHz, Chloroform-d) δ 5.18 (br, 2H), 3.80 (br, 4H), 3.65-3.62(m, 8H), 3.54-3.52 (m, 2H), 3.36 (s, 3H), 2.63 (s, 2H), 2.55 (br, 2H),2.55 (br, 4H). LC-MS: 361.2 (MH⁺/z).

Synthesis of 3-N-(4′-N-mPEG₃-piperazinyl) lamotrigine (Compound 103)

5-Amino-6-chloro-3-(N-mPEG₃-piperazinyl)amino-1,2,4-triazine (239.3 mg,0.66 mmol) was dissolved in dioxane (15 mL). (2,3-Dichlorophenyl)boronicacid (242.6 mg, 1.27 mmol) and cesium carbonate (691.7 mg, 2.10 mmol)were added. And then water (5 mL) was added. The mixture was degassedwith nitrogen, tetrakis(triphenylphosphine)palladium (42.2 mg, 0.037mmol) was added. The mixture was purged with nitrogen for a few minutes,and then heated to 85° C. during 55 min, and kept at 85° C. for 1 h. Themixture was concentrated under reduced pressure to dryness. The residuewas mixed with water, extracted with dichloromethane (4×20 mL). Theorganic solution was concentrated. The residue was purified with flashcolumn chromatography on silica gel to afford product (135.7 mg, Yield:43%). ¹H NMR (500 MHz, Chloroform-d) δ 7.546 (dd, J=1.5 and 7.5 Hz, 1H,Ar—H), 7.351 (m, 2H, Ar—H), 4.689 (br, 2H, NH₂), 3.891 (br, 4H, 2 CH₂),3.666-3.625 (m, 8H, 4CH₂), 3.545-3.527 (m, 2H, CH₂), 3.367 (s, 3H, CH₃),2.637 (t, J=6.0 Hz, 2H, CH₂), 2.578 (t, J=5.0 Hz, 4H, 2CH₂). LC-MS:471.0 (MH⁺/z).

Some of product was dissolved in dichloromethane (3 mL), 2 Nhydrochloride in ether (1.5 mL) was added to afford white solid.Acetonitrile (3 mL) was added to get cloud mixture, methanol (3 mL) wasadded to result in a clear solution. The mixture was concentrated toremove all of solvents and dried under high vacuum to afford 94.8 mg ofproduct as HCl salt. LC-MS: 471.0 (MH⁺/z).

Example 51 Preparation of Compound 104 Synthesis of3-N-(4′-N-mPEG₃-piperazinyl) 5-fluoro lamotrigine (Compound 104)Synthesis of 1-N-Boc-4-N-mPEG₃-CM-piperazine

T-Boc-piperazine (1.1369 g, 6.10 mmol) and2,5,8,11-tetraoxatridecan-13-oic acid (1.09 g, 4.90 mmol) were dissolvedin dichloromethane (10 mL). Triethylamine (3.0 mL, 21.52 mmol) wasadded, followed by addition ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.6310 g,8.51 mmol). More of dichloromethane (20 mL) was added to get a solution.The resulting mixture was stirred at room temperature for 24 h. Thereaction was taken up in 30 mL of dichloromethane, washed with brine anddried over anhydrous sodium sulfate. Solvent was removed by rotavap. Theresidue was purified on column chromatography on silica gel to affordproduct as colorless oil (1.0463 g, Yield: 55%). ¹H NMR (500 MHz,Chloroform-d) δ 4.19 (s, 2H), 3.67-3.61 (m, 10H), 3.55-3.51 (m, 4H),3.49-3.40 (m, 6H), 3.55 (s, 3H), 1.45 (s, 9H).

Synthesis of2-(2,3-dichloro-5-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-2,3-dichloro-5-fluorobenzene (3.1304 g, 12.94mmol), bis(pinacolato)diboron (5.7397 g, 22.38 mmol), potassium acetate(3.9788 g, 40.1 mmol) in DMSO (60 mL) was stirred at room temperaturefor about 30 min. The mixture was degassed with nitrogen for a fewminutes and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium (II)(0.7953 g, 1.09 mmol) was added. The mixture was degassed again withnitrogen, was heated to 80° C. with stirring and kept at 80° C. for 4 h20 min. The mixture was cooled to room temperature and poured into ice.The mixture was extracted with ethyl acetate (3×150 mL). The combinedorganic solution was washed with saturated sodium chloride solution (150mL), dried over anhydrous sodium sulfate, and concentrated. The residuewas separated with flash column chromatography on silica gel using ethylacetate/hexane to afford product as white solid (2.6156 g, Yield: 70%).¹H NMR (500 MHz, Chloroform-d) δ 7.070 (d, J=3.0 Hz, 1H), 7.029 (d,J=3.0 Hz, 1H), 1.238 (s, 12H).

Synthesis of 3-N-(4′-N-mPEG₃-piperazinyl) 5-fluoro lamotrigine

5-Amino-6-chloro 3-(N-mPEG₃-piperazinyl)amino-1,2,4-triazine (320 mg,0.89 mmol) was dissolved in dioxane (15 mL).(2,3-Dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(355.1 mg, 1.22 mmol) was added. Cesium carbonate (904.3 mg, 2.75 mmol)in water (5 mL) was added. The mixture was degassed with nitrogen,Tetrakis (triphenylphosphine)palladium (58.8 mg, 0.05 mmol) was added.The mixture was purged with nitrogen for a few minutes, and then heatedto 85° C. during 0.5 h, and kept at 85° C. for 3 h. The mixture wasconcentrated under reduced pressure to dryness. The residue was mixedwith water, extracted with dichloromethane (4×20 mL). The organicsolution was concentrated. The residue was purified with biotage onsilica gel using 4-7% methanol/dichloromethane to afford product (73.8mg, Yield: 17%). ¹H-NMR (500 MHz, CDCl₃): 7.317 (dd, J=3.0 and 8.0 Hz,1H, Ar—H), 7.129 (dd, J=3.0 and 8.0 Hz, 1H, Ar—H), 4.686 (br, 2H, NH₂),3.893 (br, 4H, 2CH₂), 3.664-3.625 (m, 8H, 4CH₂), 3.545-3.527 (m, 2H,CH₂), 3.368 (s, 3H, CH₃), 2.636 (t, J=6.0 Hz, 2H, CH₂), 2.578 (t, J=5.0Hz, 4H, 2CH₂). LC-MS: 489.0 (MH⁺/z).

The product (60 mg) was dissolved in dichloromethane (3 mL), 2 Mhydrochloride in ether (2 mL) was added, methanol (˜1 mL) was added todissolve and afford a clean solution. The mixture was concentrated toremove all of solvents and dried under high vacuum to the product as HClsalt. LC-MS: 489.0 (MH⁺/z).

Example 52 Preparation of Compound 105 Synthesis of3-N-mPEG₂-CM-piperazinyl lamotrigine (Compound 105) Synthesis oftert-butyl4-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperazine-1-carboxylate

T-Boc-piperazine (1.5837 g, 8.50 mmol) and mPEG₂-CM (1.55 mL, 10.10mmol) were dissolved in dichloromethane (100 mL). Triethylamine (3.5 mL,25.10 mmol) was added, followed by addition ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.0889 g,16.11 mmol). The resulting mixture was stirred at room temperature for24 h. The reaction was washed with brine and dried over anhydrous sodiumsulfate. Solvent was removed by rotavap. The residue was purified withcolumn chromatography on silica gel using 0-10% methanol/dichloromethaneto afford product as oil (2.4095 g, Yield: 82%). ¹H NMR (500 MHz,Chloroform-d) δ 4.20 (s, 2H), 3.69-3.64 (m, 4H), 3.62-3.61 (m, 2H),3.57-3.54 (m, 2H), 3.53-3.51 (m, 2H), 3.49-3.48 (m, 2H), 3.43-3.38 (m,4H), 3.36 (s, 3H), 1.45 (s, 9H).

Synthesis of 2-(2-(2-methoxyethoxy)ethoxy)-1-(piperazin-1-yl)ethanone

N-Boc-N′-2-(2-(2-methoxyethoxy)ethoxy)acetyl piperazine (4.5095 g, 6.96mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid(6 mL) was added. The mixture was stirred at room temperature for 2 h.The mixture was quenched with saturated aqueous potassium carbonate,brine was added. The organic solution was separated. The aqueous theaqueous solution was saturated with sodium chloride and extracted withdichloromethane. The combined organic solution dried over anhydroussodium sulfate, concentrated to afford product (1.1992 g, Yield: 70%).11H NMR (500 MHz, Chloroform-d) δ 4.19 (s, 2H), 3.70-3.65 (m, 4H),3.63-3.61 (m, 2H), 3.57 (t, J=3.0 Hz, 2H), 3.54-3.52 (m, 2H), 3.48 (t,J=3.0 Hz, 2H), 3.36 (s, 3H), 2.86-2.83 (m, 4H).

Synthesis of 5-amino-3-N-(4-mPEG₂-CMpiperazinyl)-6-chloro-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (586.3 mg,3.55 mmol) and triethylamine (1.5 mL, 10.76 mmol),2-(2-(2-methoxyethoxy)ethoxy)-1-(piperazin-1-yl)ethanone (0.898 g, 3.65mmol) in dioxane (8.0 mL). The mixture was heated at 95° C. for 1.5 husing microwave. The mixture was cooled to room temperature, filteredand the white solid was washed with dichloromethane. The organicsolution was concentrated. The residue was dissolved in dichloromethane(50 mL), washed with water. The aqueous solution was extracted withdichloromethane (30 ml). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using 1-10%methanol/dichloromethane to afford product (1.0453 g, Yield: 78%). ¹HNMR (500 MHz, Chloroform-d) δ 5.24 (br, 2H), 4.24 (s, 2H), 3.84 (t,J=3.0 Hz, 2H), 3.77 (t, J=3.0 Hz, 2H), 3.71-3.69 (m, 2H), 3.67-3.64 (m,4H), 3.63-3.61 (m, 2H), 3.59 (t, J=3.0 Hz, 2H), 3.54-3.52 (m, 2H), 3.35(s, 3H). LC-MS: 375.0 (MH⁺/z).

Synthesis of 3-N-mPEG₂-CM-piperazinyl lamotrigine

5-Amino-6-chloro-3-(N-mPEG₂-CM-piperazinyl)-1,2,4-triazine (354.5 mg,0.95 mmol) was dissolved in dioxane (18 mL). (2,3-Dichlorophenyl)boronicacid (489 mg, 2.56 mmol) and cesium carbonate (1.2194 mg, 3.71 mmol)were added. And then water (5 mL) was added. The mixture was sonicatedand degassed with nitrogen, tetrakis(triphenylphosphine)palladium (60.5mg, 0.05 mmol) was added. The mixture was purged with nitrogen for a fewminutes, and then heated to 85° C. during 25 min, and kept at 85° C. for22 h. More of the palladium catalyst (52 mg) was added. The mixture wasstirred at 85° C. for 2 h 20 min. More of the palladium catalyst (56.6mg) was added. The mixture was stirred at 85° C. for 4.5 h. More of thepalladium catalyst (65 mg) was added. The mixture was stirred at 85° C.for 1.5 h. The mixture was concentrated under reduced pressure todryness. The residue was mixed with water, extracted withdichloromethane (4×20 mL). The organic solution was concentrated. Theresidue was purified with flask column chromatography on silica gelusing methanol/dichloromethane to afford product (86.9 mg, Yield: 19%).¹H NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J=7.0, 2.5 Hz, 1H), 7.36-7.32(m, 2H), 4.75 (br, 2H), 4.26 (s, 2H), 3.94 (s, 2H), 3.87 (m, 2H),3.72-3.67 (m, 6H), 3.64-3.62 (m, 4H), 3.54-3.52 (m, 2H), 3.36 (s, 3H).LC-MS: 485.0 (MH⁺/z).

47.1 mg of product was mixed with 2 mL of acetonitrile and 2 mL ofdichloromethane. Methanol (3 mL) was added. 2 N Hydrochloride in ether(1 mL) was added to result in a clean solution. The mixture wasconcentrated to remove all of solvents and dried under high vacuum toafford product as HCl salt (49.7 mg).

Example 53 Preparation of Compound 106 Synthesis of3-N-mPEG₂-CM-piperazinyl 5′-fluoro lamotrigine (Compound 106)

5-Amino-6-chloro-3-(N-mPEG₂-CM-piperazinyl)-1,2,4-triazine (200.4 mg,0.54 mmol) and(2,3-dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(225 mg, 0.77 mmol) were mixed in dioxane (15 mL), sonicated for a fewminutes. Cesium carbonate (657.5 mg, 2.00 mmol) in water (5 mL) wasadded. The mixture was degassed with nitrogen, tetrakis(triphenylphosphine)palladium (56.1 mg, 0.05 mmol) was added. The mixture waspurged with nitrogen for a few minutes, and stirred at room temperaturefor 40 min, at 85° C. for 16 h. More of the palladium catalyst (77 mg)was added. The mixture was stirred at 85° C. for 1 h 45 min. More of thepalladium catalyst (97 mg) was added. The mixture was stirred at 85° C.for 1 h. The mixture was concentrated under reduced pressure to dryness.The residue was mixed with water, extracted with dichloromethane (4×20mL). The organic solution was concentrated. The residue was purifiedwith column chromatography on silica gel using methanol/dichloromethaneto afford crude product, which was dissolved in dichloromethane andhexane was added. The mixture was cooled to 0° C. and centrifuged toafford white solid as product (45.5 mg, Yield: 17%). ¹H NMR (500 MHz,Chloroform-d) δ 7.33 (dd, J=8.0, 2.5 Hz, 1H), 7.11 (dd, J=8.0, 2.5 Hz,1H), 4.82 (br, 2H), 4.25 (s, 4H), 3.94 (t, J=5.3 Hz, 2H), 3.87 (d, J=5.6Hz, 2H), 3.72-3.68 (m, 6H), 3.64-3.62 (m, 4H), 3.54-3.52 (m, 2H), 3.35(s, 3H). LC-MS: 503.0 (MH⁺/z).

7.6 mg of product was dissolved in methanol (1 mL), 0.5 mL of 2 Nhydrochloride in ether was added. The mixture was concentrated to removethe solvents and dried under high vacuum to product as HCl salt (4.7mg). LC-MS: 503.0 (MH⁺/z).

Example 54 Preparation of Compound 107 Synthesis of 3-N-(4′-N-mPEG₂-CMpiperidinyl) lamotrigine (Compound 107) Synthesis of tert-Butyl(1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperidin-4-yl) carbamate

4-Boc amino-piperadine (2.2842 g, 10.95 mmol) and mPEG₂-CM (2.0 mL,13.03 mmol) were dissolved in dichloromethane (60 mL). Triethylamine(4.0 mL, 28.70 mmol) was added, followed by addition ofN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (3.5165 g,18.34 mmol). The resulting mixture was stirred at room temperature for22 h. More of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.408 g) was added. The mixture was stirred at roomtemperature for 4.5 h. The reaction was washed with brine and dried overanhydrous sodium sulfate. Solvent was removed by rotavap. The residuewas purified with column chromatography on silica gel using 0-10%methanol/dichloromethane to afford product as oil (2.3017 g, Yield:58%). ¹H NMR (500 MHz, Chloroform-d) δ 4.57 (s, 1H), 4.46-4.43 (m, 1H),4.25 (d, J=13.5 Hz, 1H), 4.12 (d, J=13.5 Hz, 1H), 3.92-3.89 (m, 1H),3.74-3.61 (m, 7H), 3.57-3.51 (m, 2H), 3.37 (s, 3H), 3.07 (t, J=12.0 Hz,1H), 2.73 (t, J=12 Hz, 1H), 1.96 (d, J=6 Hz, 2H), 1.43 (s, 9H), 1.37 (m,1H), 1.31-1.21 (m, 1H).

Synthesis of1-(4-aminopiperidin-1-yl)-2-(2-(2-methoxyethoxy)ethoxy)ethanone

Tert-Butyl (1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperidin-4-yl)carbamate (2.3017 g, 6.39 mmol) was dissolved in dichloromethane (30mL). Trifluoroacetic acid (6.0 mL) was added. The resulting mixture wasstirred at room temperature for 3 h. The mixture was concentrated anddried under high vacuum for 30 min. The residue was dissolved inmethanol, and passed through a column with AG® AG MP-1 and AG-2 stronganion exchange resin. The solution was concentrated to afford product asfree base (1.6744 g, Yield: 99%). ¹H NMR (500 MHz, Chloroform-d) δ 4.42(m, 1H), 4.23-4.14 (m, 2H), 3.89-3.86 (m, 1H), 3.73-3.66 (m, 4H),3.63-3.61 (m, 2H), 3.54-3.52 (m, 2H), 3.47 (s, 1H), 3.36 (s, 3H),3.04-2.99 (m, 1H), 2.92-2.86 (m, 1H), 2.73-2.68 (m, 1H), 1.84-1.82 (m,1H), 1.29-1.18 (m, 3H).

Synthesis of5-amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperi-din-4-yl)amino-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (321.9 mg,1.95 mmol) and triethylamine (0.3 mL, 2.152 mmol),1-(4-aminopiperidin-1-yl)-2-(2-(2-methoxyethoxy) ethoxy)ethanone (0.5219g, 2.01 mmol) in dioxane (10.0 mL). The mixture was heated at 95° C. for1.5 h using microwave. More of triethylamine (0.7 mL, 5.02 mmol) wasadded. The mixture was heated again at 95° C. for 1.5 h. More oftriethylamine (0.5 mL) was added. The mixture was heated at 95° C. for45 min. The mixture was cooled to room temperature, was concentrated toremove the solvent. The residue was dissolved in dichloromethane (50mL), washed with saturated potassium carbonate. The aqueous solution wasextracted with dichloromethane (40 ml). The combined organic solutionwas washed with brine, dried over anhydrous sodium sulfate,concentrated. The residue was purified with flash column chromatographyon silica gel using 1-10% methanol/dichloromethane to afford product(176.5 mg, Yield: 23%). ¹H NMR (500 MHz, Chloroform-d) δ 5.24 (s, 2H),5.00 (br, 1H), 4.45 (d, J=13.5 Hz, 1H), 4.26 (d, J=13.4 Hz, 1H), 4.14(d, J=13.4 Hz, 1H), 4.01 (s, 1H), 3.93 (d, J=13.7 Hz, 1H), 3.74-3.57 (m,6H), 3.57-3.50 (m, 2H), 3.36 (s, 3H), 3.14 (t, J=12.1 Hz, 1H), 2.82 (t,J=12.6 Hz, 1H), 2.11-2.04 (m, 2H), 1.48 (m, 1H), 1.37 (m, 1H). LC-MS:389.2 (MH⁺/z).

Synthesis of 3-N-(4′-N-mPEG₂-CM piperidinyl) lamotrigine

5-Amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperidin-4-yl)amino-1,2,4-triazine(172 mg, 0.442 mmol) was dissolved in dioxane (10 mL).(2,3-Dichlorophenyl)boronic acid (191 mg, 1.00 mmol) and cesiumcarbonate (517.8 mg, 1.57 mmol) were added. And then water (2.5 mL) wasadded. Tetrakis(triphenylphosphine)palladium (128 mg, 0.12 mmol) wasadded. The mixture was purged with nitrogen for a few minutes, and thenheated to 85° C. during 40 min, and kept at 85° C. for 4 h. The mixturewas concentrated under reduced pressure to dryness. The residue wasmixed with water, extracted with dichloromethane (4×20 mL). The organicsolution was concentrated. The residue was purified with reverse columnchromatography on C-18 column using 15% acetonitrile/water to affordproduct (38.5 mg, Yield: 17.5%). ¹H NMR (500 MHz, Chloroform-d) δ 7.533(dd, J=3.0 Hz and 6.5 Hz, 1H), 7.328-7.237 (m, 2H), 4.985 (br, 2H),4.403 (d, J=12.5 Hz, 1H), 4.174 (q, 2H), 3.896 (d, J=13.5 Hz, 1H),3.691-3.591 (m, 6H), 3.522-3.505 (m, 2H), 3.332 (s, 3H), 3.143 (t,J=11.5 Hz, 1H), 2.841 (t, J=11.5 Hz, 1H), 2.084 (br, 2H), 1.553-1.511(m, 1H), 1.454-1.385 (m, 1H), 1.290-1.190 (m, 1H), 0.850-0.803 (m, 1H).LC-MS: 449.0 (MH⁺/z).

The product (21.6 mg) was dissolved in dichloromethane (5 mL), 0.5 mL of2N hydrochloride in ether was added. A few drops of acetonitrile wereadded to afford a clear solution, concentrated to remove all ofsolvents. The residue was dried under high vacuum to afford the productas HCl salt (22 mg). LC-MS: 449.0 (MH⁺/z).

Example 55 Preparation of Compound 108 Synthesis of3-N-(1-N-mPEG₃-piperidin-4-yl) lamotrigine (Compound 108) Synthesis of1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-amine

A solution of potassium carbonate (2.9903 g, 21.41 mmol) in water (3.5mL) was added to a mixture of 4-Boc-amino-piperadine (1.5010 g, 7.19mmol) and mPEG₃-Br (1.8364 g, 8.09 mmol) in a vial. The resultingmixture was heated at 120° C. for 1.5 h by using microwave. The mixturewas diluted with water, extracted with dichloromethane (3×30 mL). Thecombined organic solution was washed with brine, dried over anhydroussodium sulfate, concentrated. The residue was dried under high vacuum toafford tert-butyl (1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl) carbamate. ¹H NMR (500 MHz, Chloroform-d) δ4.39 (br, 1H), 3.62-3.56 (m, 8H), 3.53-3.52 (m, 2H), 3.43 (br, 1H), 3.36(s, 3H), 2.84 (d, J=12.4 Hz, 2H), 2.55 (t, J=6.0 Hz, 2H), 2.10 (t,J=11.5 Hz, 2H), 1.89 (d, J=10.5 Hz, 2H), 1.42 (s, 11H).

Tert-Butyl (1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl)carbamate was dissolved in dichloromethane (35 mL), and trifluoroaceticacid (7 mL) was added. The mixture was stirred at room temperature for 4h. More of trifluoroacetic acid (0.45 mL) was added. The mixture wasstirred at RT for 1.5 h. The mixture was concentrated to remove all ofsolvents. The residue was dried under high vacuum. The residue wasdissolved in methanol, and passed through a column with AG® 1 AG MP-1and AG-2 strong anion exchange resin. The solution was concentrated toafford product as free base in quantitative yield. ¹H NMR (500 MHz,Chloroform-d) δ 3.63-3.61 (m, 8H), 3.54-3.47 (m, 2H), 3.34 (s, 3H), 2.98(d, J=11.6 Hz, 1H), 2.75 (m, 1H), 2.65 (t, J=5.9 Hz, 1H), 2.18 (m, 1H),1.85 (m, 1H), 1.48 (m, 1H).

Synthesis of5-amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)piperidin-4-yl)amino-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (700.2 mg,4.24 mmol) and triethylamine (1.5 mL, 10.76 mmol),1-(2-(2-methoxyethoxy)ethoxy)piperidin-4-amine (1.0633 g, 4.32 mmol) indioxane (10.0 mL). The mixture was heated at 95° C. for 1.5 h usingmicrowave. The mixture was cooled to room temperature, was concentratedto remove the solvent. The residue was dissolved in dichloromethane (50mL), washed with water. The aqueous solution was extracted withdichloromethane (30 ml). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using 1-10%methanol/dichloromethane and 15% methanol/dichloromethane to affordproduct as solid (429.5 mg, 27%). ¹H NMR (500 MHz, Chloroform-d) δ 5.26(s, 2H), 4.90 (br, 1H), 3.84 (br, 1H), 3.61 (m, 8H), 3.53-3.51 (m, 2H),3.34 (s, 3H), 2.96 (m, 2H), 2.65 (m, 2H), 2.29 (m, 2H), 2.01 (m, 2H),1.52 (m, 2H). LC-MS: 375.2 (MH⁺/z).

Synthesis of 3-N-(1-N-mPEG₃-piperidin-4-yl) lamotrigine

5-Amino-6-chloro-3-(1-N-mPEG₃-piperidin-4-yl)amino-1,2,4-triazine (189.9mg, 0.51 mmol) was dissolved in dioxane (10 mL).(2,3-Dichlorophenyl)boronic acid (262.6 mg, 1.38 mmol) and cesiumcarbonate (699.6 mg, 2.13 mmol) were added. And then water (2.5 mL) wasadded. Tetrakis(triphenylphosphine)palladium (160.6 mg, 0.14 mmol) wasadded. The mixture was purged with nitrogen for a few minutes, and thenheated to 85° C. during 40 min, and kept at 85° C. for 3.5 h. Themixture was concentrated under reduced pressure to dryness. The residuewas mixed with water, extracted with dichloromethane (4×20 mL). Theorganic solution was concentrated. The residue was purified with columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford product (166.2 mg, Yield: 68%).

¹H NMR (500 MHz, Chloroform-d) δ 7.551 (dd, J=2.0 Hz and 7.5 Hz, 1H),7.362-7.308 (m, 1H), 4.735 (br, 2H), 3.920 (br, 1H), 3.648-3.609 (m,10H), 3.545-3.526 (m, 2H), 3.362 (s, 3H), 2.914 (br, 2H), 2.604 (br,2H), 2.245 (br, 2H), 2.058 (br, 2H), 1.611 (m, 3H). LC-MS: 485.0(MH⁺/z).

Product (100.2 mg) was dissolved in a mixture of acetonitrile (3mL)/dichloromethane (3 mL), about 1 mL of 2 N hydrochloride in ether wasadded. The mixture was concentrated to remove all of solvents, driedunder high vacuum to afford product as HCl salt (94.6 mg). LC-MS: 485.0(MH⁺/z).

Example 56 Preparation of Compound 109 Synthesis of 3-N-(4′-N-mPEG₂-CMpiperidinyl) 5′-fluoro lamotrigine (Compound 109)

5-Amino-6-chloro-3-N-(1-(2-(2-(2-methoxyethoxy)ethoxy)acetyl)piperidin-4-yl)amino-1,2,4-triazine(176 mg, 0.45 mmol) was dissolved in dioxane (10 mL). Pinacol(2,3-dichloro-5-fluorophenyl)boronic ester (308.5 mg, 1.06 mmol) andcesium carbonate (561.2 mg, 1.71 mmol) were added. And then water (2.5mL) was added. Tetrakis-(triphenylphosphine)palladium (114.5 mg, 0.10mmol) was added. The mixture was purged with nitrogen for a few minutes,and then heated to 85° C. during 25 min, and kept at 85° C. for 2.5 h.The mixture was concentrated under reduced pressure to dryness. Theresidue was mixed with water, extracted with dichloromethane (4×20 mL).The organic solution was concentrated. The residue was purified withcolumn chromatography on silica gel using 1-10% methanol/dichloromethaneto afford product (113.4 mg, Yield: 48%). ¹H-NMR (500 MHz, Methanol-d₄)δ 7.541 (dd, J=3.0 Hz and 8.0 Hz, 1H), 7.224 (dd, J=3.0 Hz and 8.0 Hz,1H), 4.90 (br, 2H), 4.434 (d, J=13.0 Hz, 1H), 4.32 (d, J=13.9 Hz, 1H),4.23 (d, J=13.8 Hz, 1H), 4.101-4.058 (m, 1H), 3.951 (d, J=14.3 Hz, 1H),3.708-3.676 (m, 4H), 3.644-3.625 (m, 2H), 3.556-3.538 (m, 2H), 3.360 (s,3H), 3.207 (t, J=1.2.5 Hz, 1H), 2.882 (t, J=11.5 Hz, 1H), 2.078 (t,J=13.5 Hz, 2H), 1.618-1.548 (m, 1H), 1.519-1.442 (m, 1H). LC-MS: 517.0(MH⁺/z).

The product (˜41 mg) was mixed with acetonitrile (3 mL). Methanol (5 mL)was added and warmed up to afford a clear solution. 2N Hydrochloride inether (1 mL) was added. The mixture was concentrated to remove thesolvents and dried under high vacuum to afford product as HCl salt (42.5mg).

Example 57 Preparation of Compound 110 Synthesis of3-N-(1-N-mPEG₃-piperidin-4-yl) 5′-fluoro lamotrigine (Compound 110)

5-Amino-6-chloro-3-(1-N-mPEG₃-piperidin-4-yl)amino-1,2,4-triazine (156mg, 0.42 mmol) was dissolved in dioxane (10 mL). Pinacol(2,3-dichloro-5-fluorophenyl)boronic ester (278.8 mg, 0.96 mmol) andcesium carbonate (523.4 mg, 1.59 mmol) were added. And then water (2.5mL) was added. Tetrakis(triphenylphosphine)palladium (126.7 mg, 0.11mmol) was added. The mixture was purged with nitrogen for a few minutes,and then heated to 85° C. during 25 min, and kept at 85° C. for 2 h. Themixture was concentrated under reduced pressure to dryness. The residuewas mixed with water, extracted with dichloromethane (4×20 mL). Theorganic solution was concentrated. The residue was purified with columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford product (121.9 mg, Yield: 58%). ¹H NMR (500 MHz, Chloroform-d) δ7.314 (dd, J=3.0 Hz and 8.0 Hz, 1H), 7.123 (dd, J=3.0 Hz and 8.0 Hz,1H), 4.922 (br, 2H), 3.920 (br, 1H), 3.674-3.646 (m, 2H), 3.620-3.602(m, 61H), 3.529-3.510 (m, 2H), 3.344 (s, 3H), 3.012 (br, 2H), 2.692 (br,2H), 2.359 (br, 2H), 2.079 (br, 2H), 1.735-1.716 (m, 2H). LC-MS: 503.0(MH⁺/z).

The product was mixed with acetonitrile (3 mL) and dichloromethane (3mL). 1.5 mL of 2 N hydrochloride in ether was added. The mixture wasconcentrated to remove all of solvents and dried under high vacuum toafford the product as HCl salt (119.1 mg).

Example 58 Preparation of Compound 111 Synthesis of3-N-(4-N-mPEG₃-3,5-dimethylpiperazinyl) lamotrigine (Compound 111)Synthesis of 1-N-mPEG₃-2,6-dimethylpiperazine

A solution of potassium carbonate (1.4370 g, 10.40 mmol) in water (3 mL)was added to a mixture of 1-N-t-Boc-3,5-dimethyl piperazine (0.6882 g,3.21 mmol) and mPEG₃-Br (0.8872 g, 3.91 mmol) in a vial. The resultingmixture was heated at 120° C. for 1.5 h by using microwave. The mixturewas diluted with water, extracted with dichloromethane (3×30 mL). Thecombined organic solution was washed with brine, dried over brine,concentrated. The residue was dried under high vacuum. The residue wasseparated with flash column chromatography on silica gel column using1-5% methanol/dichloromethane, and NH-column using 0-5%methanol/dichloromethane to afford the intermediate.

The intermediate was dissolved in dichloromethane (8 mL), andtrifluoroacetic acid (5 mL) was added. The mixture was stirred at roomtemperature for 6 h. Water was added. The organic solution was removedand the aqueous solution was washed again with dichloromethane. Theaqueous solution was treated with 1N sodium hydroxide solution until abasic solution was obtained, sodium chloride was added to saturate theaqueous solution, extracted with dichloromethane (5×20 mL). The combinedorganic solution was dried over anhydrous sodium sulfate, concentratedto afford a oil as final product (175.4 mg). ¹H NMR (500 MHz,Chloroform-d) δ 3.635-3.575 (m, 6H), 3.540-3.490 (m, 4H), 3.360 (s, 3H),2.880 (t, J=7.5 Hz, 2H), 2.816 (d, J=11.0 Hz, 2H), 2.546-2.486 (m, 2H),2.449 (t, J=11.5 Hz, 2H), 1.035 (d, J=6.0 Hz, 6H).

Synthesis of5-amino-6-chloro-3-N-(4-mPEG₃-3,5-dimethylpiperazinyl)amino-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (114.4 mg,0.69 mmol) and triethylamine (0.4 mL, 2.87 mmol),1-N-mPEG₃-2,6-dimethylpiperazine (0.1742 g, 0.67 mmol) in dioxane (2.5mL). The mixture was heated at 95° C. for 1.5 h using microwave. Themixture was cooled to room temperature, filtered and the white solid waswashed with dichloromethane. The organic solution was concentrated. Theresidue was dissolved in dichloromethane, washed with saturatedpotassium carbonate, dried over anhydrous sodium sulfate, concentrated.The residue was purified with flash column chromatography on silica gelusing ethyl acetate and 0-10% methanol/ethyl acetate to afford productas oil (226.8 mg, Yield: 87%). ¹H NMR (500 MHz, Chloroform-d) δ 5.257(s, 2H), 4.412 (br, 2H), 3.595-3.547 (m, 6H), 3.509-3.467 (m, 4H), 3.334(s, 3H), 2.898 (t, J=7.5 Hz, 2H), 2.654-2.584 (m, 4H), 1.112 (d, J=5.5Hz, 6H). LC-MS: 389.2 (MH⁺/z).

Synthesis of 3-N-(4-N-mPEG₃-3,5-dimethylpiperazinyl) lamotrigine

5-amino-6-chloro-3-N-(4-mPEG₃-3,5-dimethylpiperazinyl)amino-1,2,4-triazine(226.8 mg, 0.66 mmol) was dissolved in dioxane (15 mL).(2,3-Dichlorophenyl)boronic acid (265.3 mg, 1.39 mmol) and cesiumcarbonate (739.3 mg, 2.25 mmol) were added. And then water (5 mL) wasadded. The mixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (86 mg, 0.074 mmol) was added. Themixture was purged with nitrogen for a few minutes, and then heated to90° C. during 55 min, and kept at 90° C. for 4 h 10 min. The mixture wasconcentrated under reduced pressure to dryness. The residue was mixedwith water, extracted with dichloromethane (4×20 mL). The organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 30-100% ethyl acetate/hexane and1-10% methanol/ethyl acetate to afford product as solid (215.3 mg,Yield: 74%).

Take 0.115 g of product to dissolve in methanol (1.0 mL), 0.5 mL of 2 Nhydrochloride in ether was added. The mixture was concentrated to removethe solvents and dried under high vacuum to afford the product as HClsalt (135.4 mg). ¹H NMR (500 MHz, Chloroform-d) δ 7.543 (dd, J=2.0 Hzand 8.0 Hz, 1H), 7.355-7.300 (m, 2H), 4.681 (s, 2H), 4.588 (br, 2H),3.616-3.590 (m, 6H), 3.532-3.514 (m, 4H), 3.353 (s, 3H), 2.946 (t, J=6.5Hz, 2H), 2.697 (m, 4H), 1.163 (d, J=3.0 Hz, 6H). LC-MS: 499.2 (MH⁺/z).

Example 59 Preparation of Compounds 112 and 164 Synthesis of4-O-mPEG₃-lamotrigine Synthesis of 6-chloro-3,5-diamino-1,2,4-triazine

A vial was placed 5-amino-3,6-trichloro-1,2,4-triazine (1.5805 g, 8.57mmol). THF was added to dissolve the yellow solid. 10 mL of ammoniumhydroxide was added. The mixture was stirred at 0° C. for a few min. Thevial was heated at 95° C. using microwave for 1 h. The mixture wascooled to room temperature, concentrated to remove the organic solvent.The remaining mixture was filtrated and washed with water. The yellowsolid was collected and dried to afford product (1.6221 g, Yield: 69%).¹H NMR (500 MHz, DMSO-d₆) δ 7.622 (br, 2H), 7.113 (br, 2H). ¹³C-NMR (500MHz, DMSO-d₆) δ 162.06, 153.10, 132.66.

Synthesis of 4-methoxy lamotrigine

A mixture of (2,3-dichloro-4-methoxyphenyl) boronic acid (323.8 mg, 1.44mmol), 3,5-diamino-6-chloro-1,2,4-triazine (170 mg, 1.17 mmol), cesiumcarbonate (989.4 mg, 3.01 mmol) andtetrakis(triphenylphosphine)palladium (100.4 mg, 0.09 mmol) indioxane/water (10 mL/2 mL) was heated at 85° C. for 6.5 h. The mixturewas concentrated under reduced pressure to dryness. The residue wasmixed with water, and dichloromethane. The mixture was filtered andwashed with dichloromethane. The solid was collected to afford product(331.5 mg, Yield: 99%) ¹H NMR (500 MHz, DMSO-d₆) δ 7.324 (d, J=6.0 Hz,1H), 7.237 (d, J=6.0 Hz, 1H), 6.59 (br, 1H), 6.366 (br, 3H), 3.934 (s,3H). LC-MS: 286.0 (MH⁺/z).

Synthesis of 4-hydroxy lamotrigine

4-Methoxy-lamotrigine (290.5 mg, 1.02 mmol) was mixed with anhydrousdichloromethane (15 mL) at room temperature, and then 5 mL of borontribromide solution 1.0 M in dichloromethane (5 mmol) was added: Theresulting mixture was stirred at room temperature for 5.5 h. More ofboron tribromide solution (5 mL) was added. The mixture was stirred atroom temperature for 17 h. More of boron tribromide solution (2 mL) wasadded. The mixture was stirred at room temperature for 5 h. The mixturewas quenched by slow addition of methanol. The mixture was concentratedto remove all of organic solvents. The remaining mixture was mixed withammonia (˜20 mL) and stirred at room temperature for 17.5 h. The mixturewas concentrated to remove all of solvents. The material was purifiedwith flash column chromatography on silica gel using 1-30%methanol/dichloromethane to afford product as slight powder (122.7 mg,Yield: 44%). ¹H NMR (500 MHz, DMSO-d₆) δ 10.794 (s, 1H), 7.141 (d, J=8.5Hz, 1H), 7.021 (d, J=8.5 Hz, 1H), 6.401 (s, 2H). LC-MS: 270.1 (MH⁺/z).

Synthesis of 4-O-mPEG₃-lamotrigine (Compound 112)

The mixture of 4-hydroxy-lamotrigine (68.2 mg, 0.25 mmol), mPEG₃-Br(68.5 mg, 0.30 mmol) and potassium carbonate (125.6 mg, 0.91 mmol) inDMF (5 ml) was stirred at 65° C. for 6 h. Water was added to quench thereaction. The mixture was extracted with ethyl acetate (2×60 mL). Thecombined organic solution was washed with brine, dried over anhydroussodium sulfate, concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford product as white solid (65.1 mg, Yield: 62%).

¹H NMR (500 MHz, Methanol-d₄) δ 7.312 (d, J=8.5 Hz, 1H), 7.206 (d, J=8.5Hz, 1H), 4.308-4.290 (m, 2H), 3.936-3.918 (m, 2H), 3.774-3.756 (m, 2H),3.677-3.636 (m, 4H), 3.541 (dd, J=5.6, 3.7 Hz, 2H), 3.307 (s, 3H).LC-MS: 418.0 (MH⁺/z).

Example 60 Preparation of Compound 113 Synthesis of3-N-(4-N,N-methyl-mPEG₃-amino)piperidin-1-yl) lamotrigine (Compound11.3) Synthesis of 1-N-Boc-4-(N,N-methyl-mPEG₃)amino piperidine

A mixture of 1-N-t-Boc-4-methylamino piperidine (1.0458 g, 4.88 mmol)and mPEG₃-Br (1.2490 g, 5.50 mmol) and potassium carbonate (1.8871 g,13.65 mmol) in water (2.0 mL) in a vial was heated at 120° C. for 1.5 hby using microwave. The mixture was diluted with water, extracted withdichloromethane (3×30 mL). The combined organic solution was washed withbrine, dried over anhydrous sodium sulfate, concentrated. The residuewas dried under high vacuum. The residue was separated with flash columnchromatography on silica gel using 1-5% methanol in dichloromethane toafford product (1.2531 g) as oil in 78% yield. ¹H NMR (500 MHz,Chloroform-d) δ 4.11 (s, 2H), 3.65-3.56 (m, 6H), 3.55-3.49 (m, 4H), 3.35(s, 3H), 2.63 (br, 2H), 2.62 (t, J=6.2 Hz, 2H), 2.49 (m, 1H), 2.27 (s,3H), 1.70 (d, J=12.7 Hz, 2H), 1.42 (s, 9H), 1.44-1.30 (m, 2H). MS forC₁₈H₃₆N₂O₅: 361.2 (MH⁺).

Synthesis of 4-(N,N-methyl-mPEG₃)amino piperidine

1-Boc-4-(N,N-methyl-mPEG₃)amino piperidine (1.2531 g, 3.48 mmol) wasdissolved in dichloromethane (10 mL). Trifluoroacetic acid (3 mL) wasadded. The resulting mixture was stirred at room temperature for 4 h.The mixture was concentrated to remove the solvent. The residue wasdissolved in dichloromethane, treated with aqueous potassium hydroxideuntil the aqueous solution was basic. Some brine was added. The organicsolution was separated and the aqueous solution was extracted withdichloromethane (2×30 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated to afford the product (774 mg) in86% yield. ¹H NMR (500 MHz, Chloroform-d) δ 3.67-3.55 (m, 6H), 3.55-3.48(m, 4H), 3.34 (s, 3H), 3.09 (dt, J=11.9, 2.5 Hz, 2H), 2.63 (t, J=6.3 Hz,2H), 2.51 (dt, J=12, 2.5 Hz, 2H), 2.46-2.37 (m, 1H), 2.26 (s, 3H),1.76-1.68 (m, 2H), 1.35 (qd, J=12.2, 4.0 Hz, 2H).

Synthesis of 5-amino-6-chloro-3-(4-(N,N-methyl (mPEG₃)amino)piperidin-1-yl)-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (471.0 mg,2.85 mmol), triethylamine (1.5 mL, 10.76 mmol), 4-(N,N-methyl-mPEG₃)amino piperidine (774.0 mg, 2.97 mmol) in dioxane (10 mL). The mixturewas heated at 95° C. for 1.5 h using microwave. The mixture was cooledto room temperature and transferred into a flask with dichloromethane,concentrated to remove the solvents. The residue was mixed with brine,extracted with dichloromethane (3×40 mL). The combined organic solutionwas dried over anhydrous sodium sulfate, concentrated. The residue wasseparated with flash column chromatography on silica gel using 1-10%methanol in dichloromethane to afford the product (1.0055 g) in 91%. ¹HNMR (500 MHz, Chloroform-d) δ 5.18 (s, 2H), 4.74 (d, J=13.2 Hz, 2H),3.66-3.59 (m, 6H), 3.58-3.50 (m, 4H), 3.36 (s, 3H), 2.81 (td, J=12.9,2.5 Hz, 2H), 2.67 (br, 3H), 2.30 (s, 3H), 1.83 (d, J=12.5 Hz, 2H), 1.45(qd, J=12.3, 4.3 Hz, 2H). MS for C₁₆H₂₉ClN₆O₃: 389.2 (MH⁺).

Synthesis of 3-N-(4-N,N-methyl-mPEG₃-amino)piperidin-1-yl) lamotrigine(Compound 113)

(2,3-Dichlorophenyl)boronic acid (476.8 mg, 2.499 mmol) and5-amino-6-chloro-3-(4-(N,N-methyl (mPEG₃)amino)piperidin-1-yl)-1,2,4-triazine (349.7 mg, 0.899 mmol) wasdissolved in water/dioxane (5/15 mL). Cesium carbonate (1.0573 g, 3.21mmol) was added. The mixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (99.7 mg, 0.086 mmol) was added.The mixture was purged with nitrogen for a few minutes, and then heatedto 90° C. during 15 min, and kept at 90° C. for 4 h. The mixture wasconcentrated under reduced pressure to dryness. The residue was mixedwith brine, extracted with dichloromethane (4×20 mL). The organicsolution was concentrated. The residue was purified with columnchromatography using 1-5% methanol in dichloromethane to afford product(244.6 mg) in 55% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.54 (dd,J=8.3, 1.8 Hz, 1H), 7.38-7.28 (m, 2H), 4.90 (d, J=13.0 Hz, 2H), 4.67 (s,2H), 3.62 (q, J=3.4, 2.8 Hz, 8H), 3.53 (dd, J=5.7, 3.7 Hz, 2H), 3.36 (s,3H), 2.86 (t, J=12.9 Hz, 2H), 2.71 (br, 3H), 2.33 (s, 3H), 1.87 (d,J=12.5 Hz, 2H), 1.55-1.48 (m, 2H). MS for C₂₂H₃₂C₁₂N₆O₃: 499.2 (MH⁺).

3-N-(4-N,N-Methyl-mPEG₃-amino)piperidin-1-yl) lamotrigine (218 mg) wasdissolved in dichloromethane (˜6 mL), 2.0 M HCl in ether (1 mL) wasadded to result in a white suspension. Methanol (˜2 mL) was added toafford a clear solution. The solution was concentrated to remove all ofsolvents. The residue was dried under high vacuum to afford the productas HCl salt.

Example 61 Preparation of Compound 114 Synthesis of 2-Me-lamotrigine(Compound 114)

Lamotrigine (28 mg, 1.08 mmol) was dissolved in acetone (30 mL) at roomtemperature. Iodomethane (0.3 mL, 3.10 mmol) was added. The resultingmixture was stirred at room temperature for 23.5 h. After the reactioncompleted based on LC-MS, the reaction mixture was filtrated and washedwith acetone. About 225 mg white solid was obtained, the solution wasconcentrated to afford a yellow solid. Both solids were combined anddried under high vacuum. The solid was stirred with ammonia (25 mL) for4 h. The mixture was filtered and washed with water. The solid waslyophilized overnight to result in 227.2 mg of product. ¹H NMR (500 MHz,Chloroform-d) δ 7.58 (dd, J=8.0, 1.6 Hz, 1H), 7.37-7.28 (m, 2H), 3.67(s, 3H). LC-MS: 270.0 (MH⁺/z).

About 15 mg of product (0.05 mmol) was dissolved in methanol (˜5 mL).Methanesulfonic acid (20 μL, 0.3 mmol) was added. The mixture wasconcentrated to remove all of solvent and dried under high vacuum. ¹HNMR (500 MHz, DMSO-d₆) δ 9.22 (s, 1H), 8.84 (br, 1H), 8.32 (br, 1H),8.26 (s, 1H), 7.96 (d, J=8.0, 1.2 Hz, 1H), 7.69-7.58 (m, 2H), 3.85 (s,3H). LC-MS: 270.0 (MH⁺/z).

In one or more embodiments, the compounds of the invention are asdescribed herein with the provisio that the compounds do not includeCompound 114.

Example 62 Preparation of Compound 115 Synthesis of 3-N-piperidin-4-yllamotrigine (Compound 115) Synthesis of5-amino-3,6-dichloro-1,2,4-triazine

3,5,6-Trichloro-1,2,4-triazine (4.6114 g, 24.28 mmol) was dissolved inTHF (100 mL) at room temperature. And then triethylamine (5.0 mL, 35.9mmol) was added. The mixture was cooled to 0° C., ammonia in dioxane(0.5 M, 51 mL, 25.5 mmol) was added. The mixture was stirred at 0° C.for 30 min, at room temperature for 5 h. The mixture was filtered toremove the solid. The solid was washed with ethyl acetate. The combinedorganic solution was concentrated. The crude mixture was mixed withabout 50 mL of ethyl acetate and warmed up, and then cooled to roomtemperature. The solid was collected and washed with ether to afford thefirst partial product. The solution was concentrated to remove all ofsolvents. The residue was mixed with about 5 ml of ethyl acetate, thesolid was collected and dried. The solution was purified with flashcolumn chromatography on silica gel using 35-100% ethyl acetate/hexanesto afford 3rd part of solid. The total of product was 3.8998 g and theyield was 97%. LC-MS: 165.1 (MH⁺/z).

Synthesis of5-amino-6-chloro-3-(1-N-tert-Boc-piperidin-4-yl)amino-1,2,4-triazine

A flask was charged with 5-amino-3,6-dichloro-1,2,4-triazine (1.2659 g,7.67 mmol) and 4-amino-1-t-Boc-piperidine (1.5894 g, 7.70 mmol) indioxane (50 mL). Triethylamine (3.0 mL, 21.52 mmol) was added, themixture was heated to 95° C. within 15 min and kept at 95° C. for 2 h,at 100° C. for 3.5 h. The mixture was cooled to room temperature,filtered and the white solid was washed with ethyl acetate. The organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford product (998 mg, Yield: 40%). ¹H NMR (500 MHz, Chloroform-d) δ5.252 (br, 2H), 4.909 (br, 1H), 4.024-3.914 (m, 3H), 2.895 (m, 3H),2.010-1.989 (m, 2H), 1.444 (s, 9H), 1.398-1.315 (m, 2H). LC-MS: 329.0(MH⁺/z).

Synthesis of 3-N-piperidin-4-yl lamotrigine (Compound 115)

Tert-Butyl4-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)piperidine-1-carboxylate(250 mg, 0.76 mmol), (2,3-dichlorophenyl)boronic acid (392.9 mg, 2.06mmol) and cesium carbonate (703.2 mg, 2.14 mmol) was dissolved indioxane/water (10 mL/2.5 mL). Tetrakis(triphenyl phosphine)palladium(284.2 mg, 0.25 mmol) was added. The mixture was purged with nitrogenfor a few minutes, and then heated to 85° C. during 25 min, and kept at85° C. for 3.5 h. The mixture was concentrated under reduced pressure todryness. The residue was mixed with water, extracted withdichloromethane (4×20 mL). The organic solution was concentrated. Theresidue was purified with column chromatography on silica gel using1-10% methanol/dichloromethane to afford product (162.5 mg, Yield: 49%).

The product was dissolved in dichloromethane (5 mL), about 2 mL oftrifluoroacetic acid was added. The mixture was stirred at roomtemperature for 6.5 h. The mixture was concentrated to remove thesolvents. The residue was dissolved in dichloromethane (20 mL), washedwith saturated potassium carbonate, brine, dried over anhydrous sodiumsulfate, concentrated. The residue was purified with NH-column using1-15% methanol/dichloromethane and recrystallized withmethanol/dichloromethane/hexane to afford product (54 mg). ¹H-NMR (500MHz, CDCl₃): 7.553 (d, J=2.0 Hz and 8.0 Hz, 1H), 7.367-7.310 (m, 2H),4.713 (br, 2H), 3.960 (br, 2H), 3.115 (t, J=3.5 Hz, 1H), 3.089 (t, J=3.5Hz, 1H), 2.755-2.702 (m, 2H), 2.082 (m, 2H), 1.454-1.386 (m, 2H). LC-MS:339.0 (MH⁺/z).

Example 63 Preparation of Compound 79 Synthesis of 3-N-piperazin-1-yllamotrigine (Compound 79) Synthesis of5-amino-6-chloro-3-N-(4-N-Boc-piperazinyl)amino-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (466 mg,2.82 mmol) and triethylamine (1.0 mL, 7.17 mmol), t-Boc-piperazine(0.5675 g, 2.96 mmol) in dioxane. The mixture was heated at 95° C. for1.5 hours using microwave. The mixture was cooled to room temperature,filtered and the white solid was washed with ethyl acetate. The organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford 872.4 mg product as solid in 98% yield. ¹H NMR (500 MHz,Chloroform-d) δ 5.38 (br, 2H), 3.76-3.68 (m, 4H), 3.44 (dd, J=6.3, 3.9Hz, 4H), 1.42 (s, 9H). LC-MS: 315.0 (MH⁺/z).

A mixture of (2,3-dichlorophenyl)boronic acid (355.4 g, 1.86 mmol),5-amino-6-chloro-3-(4-N-BOC-piperazin-1-yl)amino-1,2,4-triazine (302.4mg, 0.96 mmol) and cesium carbonate (1.0591 g, 3.22 mmol) was dissolvedin dioxane/water (10 mL/2 mL). And thentetrakis(triphenylphosphine)palladium (112.6 mg, 0.097 mmol) was added.The mixture was purged with nitrogen for a few minutes. The mixture washeated to 90° C. during 30 min, and kept at 90° C. for 5.5 h. Themixture was cooled to room temperature, concentrated to remove theorganic solvent. The residue was dissolved in water and extracted withdichloromethane (3×40 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was separated withflash column chromatography on silica gel using 1-10%methanol/dichloromethane. The product was purified again with flashcolumn chromatography on silica gel using 30-55% ethyl acetate/hexane toafford intermediate (222.5 mg, 55%).

The intermediate (222.5 mg) was dissolved in 1.5 mL of methanol, 0.5 mLof 4 N hydrochloride in dioxane was added. The mixture was stirred atroom temperature for 4 h 40 min. More of 4 N hydrochloride in dioxane(0.3 mL) was added. The mixture was stirred at room temperature for 17.5h. The mixture was concentrated to remove the solvents. The residue wasdried under high vacuum to afford final product as HCl salt (216.1 mg).¹H NMR (500 MHz, DMSO-d₆) δ 9.61 (s, 2H), 8.99 (br, 1H), 8.07 (br, 1H),7.84 (d, J=7.9 Hz, 1H), 7.54 (t, J=7.9 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H),4.04 (s, 4H), 3.265 (s, 4H). LC-MS: 325.0 (MH⁺/z).

68.3 mg of HCl salt was mixed with saturated potassium carbonatesolution, extracted with dichloromethane (3×20 mL). The combined organicsolution was washed with brine, dried over anhydrous sodium sulfate,concentrated to afford the product as free base (47.6 mg). ¹H NMR (500MHz, Chloroform-d) δ 7.551 (dd, J=2.0 Hz and 8.0 Hz, 1H), 7.367-7.308(m, 2H), 4.689 (br, 2H), 3.862 (m, 4H), 2.954 (t, J=5.0 Hz, 4H). LC-MS:325.0 (MH⁺/z).

Example 64 Preparation of Compound 11.7 Synthesis of 3-N-piperazin-1-yl5-fluoro lamotrigine (Compound 117) Synthesis of2-(2,3-dichloro-5-fluoro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A mixture of 1-bromo-2,3-dichloro-5-fluorobenzene (3.1304 g, 12.94mmol), bis(pinacolato)diboron (5.7397 g, 22.38 mmol), potassium acetate(3.9788 g, 40.1 mmol) in DMSO (60 mL) was stirred at room temperaturefor about 30 min. The mixture was degassed with nitrogen for a fewminutes and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium (II)(0.7953 g, 1.09 mmol) was added. The mixture was degassed again withnitrogen, was heated to 80° C. with stirring and kept at 80° C. for 4 h20 min. The mixture was cooled to room temperature and poured into ice.The mixture was extracted with ethyl acetate (3×150 mL). The combinedorganic solution was washed with saturated sodium chloride solution (150mL), dried over anhydrous sodium sulfate, and concentrated. The residuewas separated with flash column chromatography on silica gel using ethylacetate/hexane to afford product as white solid (2.6156 g, Yield: 70%).¹H NMR (500 MHz, Chloroform-d) δ 7.070 (d, J=3.0 Hz, 1H), 7.029 (d,J=3.0 Hz, 1H), 1.238 (s, 12H).

A mixture of2-(2,3-dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(313.7 g, 1.08 mmol),3-(4-N-Boc-piperazin-1-yl)amino-5-amino-6-chloro-1,2,4-triazine (228.2mg, 0.73 mmol) and cesium carbonate (0.7863 g, 2.39 mmol) was dissolvedin dioxane/water (10/2 mL). And thentetrakis(triphenylphosphine)palladium (89.5 mg, 0.078 mmol) was added.The mixture was purged with nitrogen for a few minutes. The mixture washeated to 90° C., and kept at 90° C. for 5.5 h. The mixture was cooledto room temperature, concentrated to remove the organic solvent. Theresidue was dissolved in water and extracted with dichloromethane (3×40mL). The combined organic solution was dried over anhydrous sodiumsulfate, concentrated. The residue was separated with flash columnchromatography on silica gel using 30-55% ethyl acetate/hexane to affordthe intermediate (154.3 mg, Yield: 48%) and starting material (59.1 mg,recovery: 26%).

The intermediate (149.2 mg) was dissolved in 1.5 mL of methanol, 0.5 mLof 4N hydrochloride in dioxane was added. The mixture was stirred atroom temperature for 4 h 35 min. More of 4 N hydrochloride in dioxane(0.2 mL) was added. The mixture was stirred at r.t. for 1 h. The mixturewas concentrated to remove the solvents. The residue was dried underhigh vacuum to afford final product as HCl salt (161.4 mg). ¹H NMR (500MHz, Methanol-d₄) δ 7.704 (dd, J=3.0 Hz and 8.0 Hz, 1H), 7.383 (dd,J=3.0 Hz and 8.0 Hz, 1H), 4.12 (m, 4H), 3.465 (t, J=5.0 Hz, 4H). LC-MS:343.0 (MH⁺/z).

Example 65 Preparation of Compound 118 Synthesis of3-N-(3′,5′-dimethylpiperazin-1-yl) lamotrigine (Compound 118)(Stereochemistry as Shown in the Schematic) Synthesis of5-amino-3-(3,5-dimethylpiperazin-1-yl)amino-1,2-4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (495.1 mg,4.25 mmol) and triethylamine (1.5 mL, 10.76 mmol),2,6-dimethylpiperazine (0.7054 g, 4.28 mmol) in dioxane (11 mL). Themixture was heated at 95° C. for 1.5 h using microwave. The mixture wascooled to room temperature, filtered and the white solid was washed withdichloromethane. The organic solution was concentrated. The residue wasdissolved in dichloromethane, washed with saturated potassium carbonate,dried over anhydrous sodium sulfate, concentrated. The residue waspurified with flash column chromatography on silica gel using ethylacetate and 0-10% methanol/ethyl acetate to afford product as solid(0.8916 g, yield: 86%). ¹H NMR (500 MHz, Chloroform-d) δ 5.168 (br, 2H),4.550 (d, J=12.5 Hz, 2H), 2.859-2.800 (m, 2H), 2.432 (d; J=13.2 Hz, 1H),2.406 (d, J=10.5 Hz, 1H), 1.094 (d, J=6.5 Hz, 6H). LC-MS: 243.0 (MH⁺/z).

Synthesis of 3-N-(3′,5′-dimethylpiperazin-1-yl) lamotrigine (Compound118)

5-Amino-6-chloro-3-(3,5-dimethylpiperazin-1-yl)amino-1,2-4-triazine (287mg, 1.182 mmol), (2,3-dichlorophenyl)boronic acid (520.1 mg, 2.73 mmoland cesium carbonate (1.3013 g, 3.95 mmol) were added. And then water (5mL) was added. The mixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (121.5 mg, 0.105 mmol) was added.The mixture was purged with nitrogen for a few minutes, and then heatedto 90° C. during 55 min, and kept at 90° C. for 4 h 15 min. The mixturewas concentrated under reduced pressure to dryness. The residue wasmixed with brine, extracted with dichloromethane (4×20 mL). The organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane. Theproduct was purified again with reverse column chromatography using10-50% acetonitrile/water to afford the product (123.2 mg, Yield: 30%).¹H NMR (500 MHz, Chloroform-d) δ 7.550 (dd, J=2.0 Hz and 7.5 Hz, 1H),7.366-7.307 (m, 2H), 4.685 (m, 4H), 2.927-2.875 (m, 2H), 2.488 (t,J=12.0 Hz, 2H), 1.133 (d, J=6.0 Hz, 6H). LC-MS: 353.0 (MH⁺/z).

62.2 mg of product was dissolved into 1.5 mL of methanol. 0.4 mL of 2 Nhydrochloride solution in ether was added. The mixture was concentratedto dryness. The residue was dried under high vacuum to afford theproduct as HCl salt (65.2 mg).

Example 66 Preparation of Compound 119 Synthesis of3-N-(3′,5′-dimethylpiperazin-1-yl) 5′-fluoro lamotrigine (Compound 119)(stereochemistry as shown in the schematic)

5-Amino-6-chloro-3-(3,5-dimethylpiperazinyl)amino-1,2,4-triazine (179.5mg, 0.74 mmol) was dissolved in dioxane (15 mL).2-(2,3-dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(420.6 mg, 1.446 mmol) and cesium carbonate (781.4 g, 2.37 mmol) wereadded. And then water (5 mL) was added. The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (103.5 mg, 0.09 mmol)was added. The mixture was purged with nitrogen for a few minutes, andthen heated to 90° C. during 15 min, and kept at 90° C. for 5 h. Themixture was concentrated under reduced pressure to dryness. The residuewas mixed with brine, extracted with dichloromethane (4×20 mL). Theorganic solution was concentrated. The residue was purified with reversecolumn chromatography using 10-50% acetonitrile/water to afford productas white solid (98.3 mg, Yield: 36%). ¹H NMR (500 MHz, Chloroform-d) δ7.317 (dd, J=3.0 Hz and 7.5 Hz, 1H), 7.131 (dd, J=3.0 Hz and 8.0 Hz,1H), 4.696 (m, 411), 2.922-2.883 (m, 2H), 2.496 (t, J=11.5 Hz, 2H),1.134 (d, J=6.0 Hz, 6H). LC-MS: 371.0 (MH⁺/z).

Take 38.9 mg of product to dissolve in methanol (2 mL), add 2 N hydrogenchloride solution in ether (0.5 mL), and then concentrate to remove allof solvents. The residue was dried under high vacuum to afford theproduct as HCl salt (426 mg). LC-MS: 371.0 (MH⁺/z).

Example 67 Preparation of Compound 120 Synthesis of3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl) lamotrigine di HCl(Compound 120) Synthesis of5-amino-6-chloro-3-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (1.0521 g,6.38 mmol), triethylamine (4.0 mL, 28.7 mmol),1-(tetrahydro-2H-pyran-4-yl)piperazine 2HCl (1.6973 g, 6.63 mmol) indioxane (10 mL). The mixture was heated at 95° C. for 1.5 h. The mixturewas cooled to room temperature and transferred into a flask withdichloromethane, concentrated to remove the solvents. The residue wasmixed with aqueous potassium carbonate, extracted with dichloromethane(3×60 mL). The aqueous mixture was filtered to collect the solid. Thesolid was dried under high vacuum to afford first batch of product (222mg). The combined organic solution was concentrated. The residue wasdissolved in warm dichloromethane, cooled to room temperature. The solidwas collected and washed with dichloromethane to afford another batch ofproduct (1.6048 g). The total yield was 99%. 1H NMR (500 MHz,Chloroform-d) δ 5.14 (s, 2H), 3.99 (dd, J=11.3, 4.3 Hz, 2H), 3.76 (t,J=5.1 Hz, 4H), 3.34 (td, J=11.9, 1.9 Hz, 2H), 2.59-2.53 (m, 4H), 2.42(tt, J=11.4, 3.8 Hz, 1H), 1.75-1.72 (m, 2H), 1.62-1.53 (m, 2H). MS forC₁₂H₁₉ClN₆O: 299.0 (MH+).

Synthesis of 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)lamotrigine di HCl (Compound 120)

(2,3-Dichlorophenyl)boronic acid (737.8 mg, 3.87 mmol) and5-amino-6-chloro-3-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)-1,2,4-triazine(399.8 mg, 1.338 mmol) was dissolved in water/dioxane (5/15 mL). Cesiumcarbonate (1.4146 g, 4.30 mmol) was added. The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (161.8 mg, 0.140 mmol)was added. The mixture was purged with nitrogen for a few minutes, andthen heated to 90° C. during 15 min, and kept at 90° C. for 5 h. Themixture was concentrated under reduced pressure to dryness. The residuewas purified with flash column chromatography on silica gel using 3-10%methanol in dichloromethane (52.1 mg). ¹H NMR (500 MHz, Chloroform-d) δ7.55 (dd, J=7.6, 2.1 Hz, 1H), 7.38-7.29 (m, 2H), 4.69 (s, 2H), 4.03 (dd,J=11.4, 4.5 Hz, 2H), 3.89 (s, 4H), 3.38 (td, J=11.9, 1.9 Hz, 2H),2.66-2.55 (m, 4H), 2.47 (m, 1H), 1.78 (d, J=12.5 Hz, 2H), 1.61 (td,0.1=12.2, 4.5 Hz, 2H). MS for C₁₈H₂₂C₁₂N₆O: 409.0 (MH+). The product wasdissolve in dichloromethane (˜3 mL)/methanol (2 mL), 2.0 M HCl in ether(1 mL) was added. The solution was concentrated to remove all ofsolvents. The residue was dried under high vacuum to afford the productas HCl salt. MS for C₁₈H₂₂C₁₂N₆O: 409.0 (MH+).

Example 68 Preparation of Compound 121 Synthesis of3-N-(4-(piperidin-4-yl)piperazin-1-yl) lamotrigine 3HCl salt (Compound121)

(2,3-Dichlorophenyl)boronic acid (515.2 mg, 2.70 mmol) and3-amino-6-chloro-3-(1-Boc-piperidin-4-yl) piperazin-1-yl)-1,2,4-triazine(326.4 mg, 0.820 mmol) was dissolved water/dioxane (5/15 mL). Cesiumcarbonate (1.0435 g, 3.17 mmol) was added. The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (143.8 mg, 0.124 mmol)was added. The mixture was purged with nitrogen for a few minutes, andthen heated to 90° C. during 15 min, and kept at 90° C. for 3 h. Themixture was concentrated under reduced pressure to dryness. The residuewas mixed with brine, extracted with dichloromethane (2×20 mL). Theorganic solution was concentrated. The residue was purified with flashcolumn chromatography on silica gel using 1-5% methanol/dichloromethaneto afford 3-N-(1-Boc-(piperidin-4-yl)piperazin-1-yl) lamotrigine (320.8mg) in 77% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.58-7.49 (m, 1H),7.42-7.29 (m, 2H), 4.69 (s, 2H), 4.14 (br, 2H), 3.88 (s, 4H), 2.70 (s,2H), 2.62 (t, J=5.1 Hz, 4H), 2.42 (m, 1H), 1.81 (d, J=11.0 Hz, 2H), 1.43(s, 9H), 1.41 (m, 2H). MS for C₂₃H₃₁C₁₂N₇O₂: 508.2 (MH+).

3-N-(1-Boc-(piperidin-4-yl)piperazin-1-yl) lamotrigine (78 mg, 0.153mmol) was dissolved in methanol (0.5 mL), 4.0 M HCl in dioxane (1.5 mL)was added. The mixture was stirred at room temperature for 6 h. Themixture was concentrated to remove all of solvents to afford3-N-(4-(piperidin-4-yl)piperazin-1-yl) lamotrigine HCl salt as whitesolid (76.9 mg) in 97% yield. ¹H NMR (500 MHz, Deuterium Oxide) δ 7.77(dd, J=8.0, 1.5 Hz, 1H), 7.52-7.42 (m, 2H), 4.10 (br, 4H), 3.66 (d,J=12.8 Hz, 3H), 3.52 (s, 4H), 3.13 (t, J=12.7 Hz, 2H), 2.47 (d, J=13.5Hz, 2H), 1.99 (qd, J=13.2, 4.1 Hz, 2H). MS for C₁₈H₂₃C₁₂N₇: 408.0 (MH+).

3-N-(4-(piperidin-4-yl)piperazin-1-yl) lamotrigine HCl salt (26.2 mg)was mixed with dichloromethane, washed with aqueous potassium carbonate.The organic solution was separated and the aqueous solution wasextracted with dichloromethane. The organic solutions were combined andwashed with brine, dried over anhydrous sodium sulfate, concentrated toafford the product as free base. ¹H NMR (500 MHz, Chloroform-d) δ 7.55(dd, J=7.7, 2.0 Hz, 1H), 7.38-7.28 (m, 2H), 4.69 (s, 2H), 3.89 (s, 4H),3.16 (d, J=12.2 Hz, 2H), 2.67-2.56 (m, 6H), 2.39 (ddt, J=11.4, 7.0, 3.5Hz, 1H), 1.84 (d, J=12.5 Hz, 2H), 1.44 (qd, J=12.2, 4.0 Hz, 2H).

Example 69 Preparation of Compound 122 Synthesis of(R)-5-amino-3-N-[3-(hydroxymethyl)piperazin-1-yl] lamotrigine diHCl(Compound 122) Synthesis of(R)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (573.3 mg,3.47 mmol), triethylamine (1.5 mL, 10.76 mmol), (R)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate (79 mg, 3.55 mmol) in dioxane(10 mL). The mixture was heated at 95° C. for 1.5 h using microwave.More of (R)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate (69.4mg) was added. The mixture was heated at 95° C. for another 1 h usingmicrowave. The mixture was cooled to room temperature and transferredinto a flask with dichloromethane, concentrated to remove the solvents.The residue was mixed with saturated potassium carbonate solution,extracted with dichloromethane (3×40 mL). The combined organic solutionwas dried over anhydrous sodium sulfate, concentrated. The residue wasmixed with small amount of dichloromethane, filtered to collect thewhite solid as first batch of product (649.6 mg). The solution wasconcentrated and the residue was separated with flash columnchromatography on silica gel using 1-5% methanol in dichloromethane toafford another batch of product (174.3 mg). The total yield was 69%. ¹HNMR (500 MHz, Chloroform-d) δ 5.32 (s, 2H), 4.71 (br, 1H), 4.47 (d,J=12.5 Hz, 1H), 4.24 (s, 1H), 3.90 (s, 1H), 3.54 (s, 1H), 3.44 (s, 1H),3.15 (d, J=14.0 Hz, 1H), 3.05 (t, J=12.0 Hz, 1H), 2.95 (s, 1H), 1.45 (s,9H). MS for C₁₃H₂₁ClN₆O₃: 345.0 (MH⁺).

Synthesis of (R)-5-amino-3-N-[3-(hydroxymethyl)piperazin-1-yl]lamotrigine diHCl

(2,3-Dichlorophenyl)boronic acid (632.8 mg, 3.32 mmol) and(R)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]1,2,4-triazine (369.0 mg, 1.07 mmol) was dissolved in water/dioxane(5/15 mL). Cesium carbonate (1.3661 g, 4.15 mmol) was added. The mixturewas degassed with nitrogen, tetrakis(triphenylphosphine)palladium (144.3mg, 0.125 mmol) was added. The mixture was purged with nitrogen for afew minutes, and then heated to 90° C. during 15 min, and kept at 90° C.for 4 h. More of catalyst (51.8 mg) was added. The mixture was stirredat 90° C. for 2 h. The mixture was concentrated under reduced pressureto dryness. The residue dissolved in dichloromethane, washed with brine,dried over anhydrous sodium sulfate, concentrated. The residue wasdissolved on methanol (5 mL). Ammonium hydroxide (10 mL) was added. Themixture was stirred at room temperature for 20 h. The mixture wasconcentrated to remove all of solvents. The residue was separated withNH-column by using 0-10% methanol in dichloromethane to afford(R)-5-amino-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl] lamotrigine (160mg) in 33% yield. MS for C₁₉H₂₄C₁₂N₆O₃: 455.0 (MH⁺).

(R)-5-amino-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl] lamotrigine (160mg, 0.351 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2.0 mL) was added. The mixture was stirred at roomtemperature for 2 h. The mixture was concentrated to remove thesolvents. The residue was dried under vacuum for a few minutes. Theresidue was dissolved in dichloromethane, washed with 5% sodiumbicarbonate aqueous solution. The organic solution was separated and theaqueous solution was extracted with dichloromethane (2×30 mL). Thecombined organic solution was dried with anhydrous sodium sulfate,concentrated to afford the product as solid (99.9 mg). ¹H NMR (500 MHz,Methanol-d₄) δ 7.66 (dd, J=8.0, 1.6 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H),7.37 (dd, J=7.6, 1.6 Hz, 1H), 4.66 (dt, J=12.7, 2.0 Hz, 1H), 4.61-4.54(m, 1H), 3.58 (qd, J=11.0, 5.7 Hz, 2H), 3.35 (s, 2H), 3.09 (dt, J=11.4,2.3 Hz, 1H), 3.09-3.00 (m, 1H), 2.83 (tt, J=10.7, 2.6 Hz, 2H), 2.77 (dd,J=12.7, 10.4 Hz, 1H). MS for C₁₆H₁₆C₁₂N₆O: 355.0 (MH⁺).

35.5 mg of product as free base was dissolved in methanol (2.0 mL), 2.0M HCl (0.5 mL) in ether was added. The resulting mixture wasconcentrated to remove all of solvents. The residue was dried under highvacuum to afford the product as HCl salt.

Example 70 Preparation of Compound 123 Synthesis of(R)-5-amino-3-N-[3-(hydroxymethyl)piperazin-1-yl] 5′-fluoro lamotriginedi HCl salt (Compound 123)

2-(2,3-Dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(387.7 mg, 1.333 mmol) and(R)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]1,2,4-triazine (240.3 mg, 0.697 mmol) was dissolved in water/dioxane(5/15 mL). Cesium carbonate (780.4 mg, 2.371 mmol) were added. Themixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (144.1 mg, 0.125 mmol) was added.The mixture was purged with nitrogen for a few minutes, and stirred at90° C. for 4.5 h. The mixture was concentrated under reduced pressure todryness. The residue dissolved in dichloromethane, washed with brine,dried over anhydrous sodium sulfate, concentrated. The residue waspurified with column chromatography on silica gel to afford(R)-5-amino-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl] 5′-fluorolamotrigine (166.7 mg) in 51% yield. MS for C₁₉H₂₃C₁₂FN₆O₃: 473.0 (MH⁺).

(R)-5-amino-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl] 5′-fluorolamotrigine (166.7 mg) (95 mg, 0.2 mmol) was dissolved indichloromethane (3 mL), trifluroacetic acid (1 mL) was added. Themixture was stirred at room temperature for 2 h. The mixture wasconcentrated to remove all of solvent. The residue was dried. Theresidue was mixed with dichloromethane, aqueous sodium bicarbonatesolution was added. The organic solution was separated and the aqueoussolution was saturated with sodium chloride, extracted withdichloromethane. The combined organic solution was dried over anhydroussodium sulfate, concentrated to afford the product as free base (59 mg)in 79% yield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.55 (dd, J=8.2, 3.0 Hz,1H), 7.23 (dd, J=8.2, 2.9 Hz, 1H), 4.71-4.64 (m, 1H), 4.59 (d, J=13.1Hz, 1H), 3.65-3.52 (m, 2H), 3.08 (ddd, J=27.4, 13.3, 3.0 Hz, 2H),2.89-2.75 (m, 3H). MS for C₁₄H₁₅Cl₂FN₆O: 373.0 (MH⁺).

54 mg of the product as free based was dissolved in methanol (1.5 mL), 2N HCl (0.5 mL) in ether was added. The mixture was concentrated toremove all of solvents. The residue was dried under high vacuum toafford the product was HCl salt (55.4 mg).

Example 71 Preparation of Compound 124 Synthesis of5-amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] lamotrigine (Compound124) Synthesis of(S)-5-amino-6-chloro-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl]1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (589.6 mg,3.57 mmol), triethylamine (1.5 mL, 10.76 mmol), (S)-tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate (890 mg, 3.99 mmol) in dioxane(12 mL). The mixture was heated at 95° C. for 1.5 h using microwave. Themixture was cooled to room temperature and transferred into a flask withdichloromethane, concentrated to remove the solvents. The residue wasmixed with saturated potassium carbonate, extracted with dichloromethane(3×40 mL). The combined organic solution was dried over anhydrous sodiumsulfate, concentrated. The residue was separated with flash columnchromatography on silica gel using 1-5% methanol in dichloromethane toafford the product (955.7 mg) in 78%. ¹H NMR (500 MHz, Chloroform-d) δ5.30 (s, 2H), 4.69 (br, 1H), 4.45 (d, J=12.3 Hz, 1H), 4.21 (s, 1H), 3.88(s, 1H), 3.52 (s, 1H), 3.42 (s, 1H), 3.13 (d, J=14.2 Hz, 1H), 3.02 (t,J=12.0 Hz, 1H), 2.93 (s, 1H), 1.43 (s, 9H). MS for C₃H₂₁ClN₆O₃: 345.2(MH⁺).

Synthesis of 5-amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] lamotrigine(Compound 124)

(2,3-Dichlorophenyl)boronic acid (363.1 mg, 1.903 mmol) and5-amino-6-chloro-3-[4-Boc-3-(s)-(hydroxymethyl)piperazin-1-yl]1,2,4-triazine (215.6 mg, 0.625 mmol) was dissolved in water/dioxane(5/15 mL). Cesium carbonate (733.6 mg, 2.229 mmol) were added. Themixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (139.6 mg, 0.121 mmol) was added.The mixture was purged with nitrogen for a few minutes, and then heatedto 90° C. during 10 min, and kept at 90° C. for 4 h. The mixture wasconcentrated under reduced pressure to dryness. The residue dissolved indichloromethane, washed with brine, dried over anhydrous sodium sulfate,concentrated. The residue was dissolved in methanol (5 mL), ammoniumhydroxide (20 mL) was added to afford a white suspension. The mixturewas stirred at r. t. for 4 h. The mixture was concentrated to remove allof solvents. The residue was separated with NH-column using 0-10%methanol in dichloromethane to afford5-amino-3-[4-Boc-3-(s)-(hydroxymethyl)piperazin-1-yl]lamotrigine (205.5mg) in 72% yield. MS for C₁₉H₂₄C₁₂N₆O₃: 455.0 (MH⁺).

(s)-5-Amino-3-[4-Boc-3-(hydroxymethyl)piperazin-1-yl] lamotrigine (140.9mg, 0.31 mmol) was dissolved in dichloromethane (3 mL). Trifluoroaceticacid (1 mL) was added. The mixture was stirred at room temperature for 2h. The mixture was concentrated to remove the solvents. The residue wasdried. The residue was mixed with dichloromethane, aqueous sodiumbicarbonate solution was added. The organic solution was separated andthe aqueous solution was saturated with sodium chloride, extracted withdichloromethane. The combined organic solution was dried over anhydroussodium sulfate, concentrated to afford5-amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] lamotrigine as free base(83.6 mg) in 76% yield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.66 (dd, J=8.0,1.6 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.37 (dd, J=7.6, 1.6 Hz, 11H),4.70-4.63 (m, 1H), 4.59 (d, J=12.9 Hz, 1H), 3.65-3.52 (m, 2H), 3.14-3.01(m, 2H), 2.89-2.75 (m, 3H). MS for C₁₄H₁₆C₁₂N₆O: 355.0 (MH⁺).

5-Amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] lamotrigine (63.5 mg)was dissolved in methanol (3 mL), filtrated through 0.2 μm filter, 2 NHCl (1.0 mL) in ether was added. The mixture was concentrated to removeall of solvents. The residue was dried under high vacuum to afford theproduct as HCl salt in quantitative yield. MS for C₁₄H₁₆C₁₂N₆O: 355.0(MH⁺).

Example 72 Preparation of Compound 125 Synthesis of5-amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] 5′-fluoro lamotrigine(Compound 125)

2-(2,3-Dichloro-5-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(349.7 mg, 1.202 mmol) and5-amino-6-chloro-3-[4-Boc-3-(s)-(hydroxymethyl)piperazin-1-yl]1,2,4-triazine (227.1 mg, 0.659 mmol) was dissolved in water/dioxane(5/15 mL). Cesium carbonate (752.5 mg, 2.286 mmol) were added. Themixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (100.2 mg, 0.087 mmol) was added.The mixture was purged with nitrogen for a few minutes, and then heatedto 90° C. during 5 min, and kept at 90° C. for 4 h 35 min. More ofcatalyst (51.7 mg) was added. The mixture was stirred at 90° C. for 18h. The mixture was concentrated under reduced pressure to dryness. Theresidue dissolved in dichloromethane, washed with brine, dried overanhydrous sodium sulfate, concentrated. The residue was purified toresult in 5-amino-3-[4-Boc-3-(s)-(hydroxymethyl)piperazin-1-yl]5′-fluoro lamotrigine (144.5 mg) in 46% yield. MS for C₁₉H₂₃Cl₂FN₆O₃:473.0 (MH⁺).

5-Amino-3-[4-Boc-3-(s)-(hydroxymethyl)piperazin-1-yl] 5′-fluorolamotrigine (81 mg) was dissolved in dichloromethane (3 mL).Trifluoroacetic acid (˜1 mL) was added. The resulting mixture wasstirred at room temperature for 1 h 10 min. The mixture was concentratedto remove all of solvents. The residue was dried. The residue was mixedwith dichloromethane, aqueous sodium bicarbonate solution was added. Theorganic solution was separated and the aqueous solution was saturatedwith sodium chloride, extracted with dichloromethane. The combinedorganic solution was dried over anhydrous sodium sulfate, concentratedto afford 5-amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] 5′-fluorolamotrigine as free base (54.6 mg). ¹H NMR (500 MHz, Methanol-d₄) δ 7.55(ddt, J=8.2, 3.0, 0.9 Hz, 1H), 7.23 (ddt, J=8.2, 2.9, 1.0 Hz, 1H), 4.68(dd, J=12.7, 2.1 Hz, 1H), 4.60 (d, J=13.1 Hz, 1H), 3.66-3.53 (m, 2H),3.16-3.03 (m, 2H), 2.93-2.77 (m, 3H). MS for C₁₄H₁₅Cl₂FN₆O: 373 (MH⁺).

5-Amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] 5′-fluoro lamotrigine(48.5 mg) was dissolved in methanol (1.5 mL) and acetonitrile (1 mL).2.0 M HCl in ether (0.5 mL) was added. The mixture was sonicated andfiltered through 0.2 μm filter. The mixture was concentrated to removeall of solvents to afford5-amino-3-[3-(s)-(hydroxymethyl)piperazin-1-yl] 5′-fluoro lamotrigine asHCl salt. MS for C₁₄H₁₅C₁₂FN₆O: 373 (MH⁺).

Example 73 Preparation of Compound 126 Synthesis of 5-amino-3-N-(3-aminoazetidinyl) lamotrigine diHCl salt (Compound 126) Synthesis of5-amino-6-chloro-3-N-(3-N-Boc-amino azetidinyl)-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (643.1 mg,3.90 mmol), triethylamine (1.5 mL, 10.76 mmol), 3-N-Boc-amino-azetidine(698.6 mg, 3.98 mmol) in dioxane (10 mL). The mixture was heated at 90°C. for 1.5 h using microwave. More of 3-N-Boc-amino-azetidine (56.2 mg,0.32 mmol) was added. The mixture was heated at 90° C. for another 45min. The mixture was concentrated to remove the solvent. The residue wasmixed with dichloromethane and aqueous sodium bicarbonate. The organicsolution was separated and the aqueous solution was extracted withdichloromethane (2×30 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated to afford white solid as productin quantitative yield. ¹H NMR (500 MHz, Chloroform-d) δ 5.25 (s, 2H),4.97 (s, 1H), 4.59 (s, 1H), 4.41 (t, J=8.0 Hz, 2H), 3.90 (dd, J=9.6, 5.2Hz, 2H), 1.42 (s, 9H). MS for C₁₁H₁₇ClN₆O₂: 301 (MH⁺).

Synthesis of 5-amino-3-N-(3-N-Boc-amino azetidinyl) lamotrigine

(2,3-Dichlorophenyl)boronic acid (1.2234 g, 6.41 mmol),5-amino-6-chlorom-3-N-(3-N-Boc-amino azetidinyl)-1,2,4-triazine (886.4mg, 0.664 mmol) and cesium carbonate (3.6613 g, 11.12 mmol) wasdissolved in water/dioxane (6.5/20 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (482.2 mg, 0.417 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 4.5 h. The mixture was concentrated to removeorganic solvents. The residue was dissolved in dichloromethane (60 mL).Water (10 mL) was added and brine (100 mL) was added. The organicsolution was separated and the aqueous solution was extracted withdichloromethane (2×70 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel to afford product (419.3 mg)in 35% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.59-7.49 (m, 1H),7.36-7.27 (m, 2H), 4.99 (s, 1H), 4.75 (s, 2H), 4.64 (s, 1H), 4.50 (s,2H), 3.98 (dd, J=9.9, 5.1 Hz, 2H), 1.44 (s, 9H). MS for C₁₇H₂₀C₁₂N₆O₂:411.0 (MH⁺).

Synthesis of 5-amino-3-N-(3-amino azetidinyl) lamotrigine diHCl salt:(Compound 73)

5-Amino-3-N-(3-N-Boc-amino azetidinyl) lamotrigine (418 mg, 1.016 mmol)was dissolved in dichloromethane (12 mL). Trifluoroacetic acid (2.0 mL)was added. The resulting mixture was stirred at room temperature for 5 h50 min. The mixture was concentrated to remove all of solvents. Theresidue was dried under high vacuum for a few minutes. The residue wasmixed with aqueous sodium bicarbonate, saturated with sodium chloride,extracted with dichloromethane. The organic solution was separated andthe aqueous solution was extracted with dichloromethane. The combinedorganic solution was dried over anhydrous sodium sulfate, concentratedto afford product as white solid (296 mg) in 94% yield. ¹H NMR (500 MHz,Chloroform-d) δ 7.55 (dd, J=7.3, 2.4 Hz, 1H), 7.37-7.27 (m, 3H), 4.73(s, 3H), 4.45 (t, J=8.3 Hz, 3H), 4.03-3.94 (m, 1H), 3.84 (dd, J=9.4, 5.2Hz, 3H), 3.47 (s, 1H), 1.23 (s, 2H). MS for C₁₂H₁₂C₁₂N₆: 311.0 (MH⁺).

5-Amino-3-N-amino azetidinyl lamotrigine (49 mg, 0.157 mmol) wasdissolved in methanol to afford a clear solution. 2.0 M HCl in ether(0.4 mL, 0.8 mmol) was added. The mixture was concentrated to remove allof solvents to afford product as HCl salt. MS for C₁₂H₁₂C₁₂N₆: 311.0(MH⁺).

Example 74 Preparation of Compound 127 Synthesis of(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127) Synthesis of(R)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (457.7 mg,2.77 mmol), triethylamine (2.0 mL, 14.35 mmol),(R)-hexahydro-oxazolo[3,4-a]pyrazin-3-one HCl (551.8 mg, 3.09 mmol) indioxane (10 mL). The mixture was heated at 90° C. for 1.5 h usingmicrowave, 120° C. for 60 min. The mixture was concentrated to removeall of solvent. The residue was dissolved in dichloromethane, washedwith aqueous sodium bicarbonate solution. The aqueous solution wasextracted with dichloromethane (2×30 mL). The combined organic solutionwas washed with brine, dried over anhydrous sodium sulfate,concentrated. The red residue was mixed with small amount ofdichloromethane (˜10 mL), warmed up and cooled to room temperature. Thesolid was collected as product (296.4 mg). ¹H NMR (500 MHz,Chloroform-d) δ 5.24 (br, 2H), 4.95-4.88 (m, 1H), 4.70 (d, J=12.4 Hz,1H), 4.44 (t, J=8.6 Hz, 1H), 3.99 (dd, J=9.0, 5.5 Hz, 1H), 3.89-3.82 (m,2H), 3.06 (td, J=12.7, 3.7 Hz, 1H), 2.93 (td, J=12.8, 3.7 Hz, 1H), 2.81(dd, J=13.0, 11.1 Hz, 1H). MS for C₉H₁₁ClN₆O₂: 271.0 (MH⁺).

Synthesis of(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127)

(2,3-Dichlorophenyl)boronic acid (285.2 mg, 1.495 mmol) and(R)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(179.6 mg, 0.664 mmol) was dissolved in water/dioxane (5/15 mL). Cesiumcarbonate (722.5 mg, 2.195 mmol) were added. The mixture was degassedwith nitrogen, tetrakis(triphenylphosphine)palladium (120.2 mg, 0.104mmol) was added. The mixture was purged with nitrogen for a few minutes,and stirred at 90° C. for 5 h. The mixture was concentrated to removeorganic solvents. The residue was dissolved in dichloromethane (30 mL).Water (10 mL) was added and brine (40 mL) was added. The organicsolution was separated and the aqueous solution was extracted withdichloromethane (2×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using 30-100% ethylacetate/hexane to afford product as white solid (155.8 mg) in 62% yield.¹H NMR (500 MHz, Chloroform-d) δ 7.60-7.53 (m, 1H), 7.37-7.29 (m, 2H),5.07 (d, J=12.7 Hz, 1H), 4.85 (d, J=13.7 Hz, 1H), 4.77 (s, 2H), 4.45(dd, J=8.9, 8.2 Hz, 1H), 4.01 (dd, J=9.0, 5.6 Hz, 1H), 3.95-3.84 (m,2H), 3.11 (td, J=12.8, 3.7 Hz, 1H), 2.96 (td, J=12.8, 3.7 Hz, 1H), 2.84(dd, J=13.0, 11.0 Hz, 1H). MS for C₁₅H₁₄C₁₂N₆O₂: 381.0 (MH⁺).

(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(88.6 mg, 0.232 mmol) was dissolved in a mixture of methanol,acetonitrile and dichloromethane to afford a clear solution. 2.0 M HClin ether (0.6 mL, 1.2 mmol) was added. The mixture was concentrated toremove all of solvents to afford product as HCl salt.

Example 75 Preparation of Compound 128 Synthesis of(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128) Synthesis of(S)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (458.3 mg,2.78 mmol), triethylamine (2.0 mL, 14.35 mmol),(s)-hexahydro-oxazolo[3,4-a]pyrazin-3-one HCl (561.8 mg, 3.05 mmol) indioxane (10 mL). The mixture was heated at 120° C. for 60 min usingmicrowave. The mixture was concentrated to remove all of solvent. Theresidue was dissolved in dichloromethane, washed with aqueous sodiumbicarbonate solution. The aqueous solution was extracted withdichloromethane (5×30 mL). The combined organic solution was washed withbrine, dried over anhydrous sodium sulfate, concentrated to affordproduct (720.8 mg) in 96% yield. ¹H NMR (500 MHz, Chloroform-d) δ 5.27(s, 2H), 4.92 (d, J=10.4 Hz, 1H), 4.71 (d, J=12.7 Hz, 1H), 4.45 (t,J=8.6 Hz, 1H), 3.99 (dd, J=9.0, 5.5 Hz, 1H), 3.89-3.80 (m, 2H), 3.06(td, J=12.7, 3.7 Hz, 1H), 2.93 (td, J=12.8, 3.7 Hz, 1H), 2.81 (dd,J=13.0, 11.1 Hz, 1H). MS for C₉H₁₁ClN₆O₂: 271.0 (MH⁺).

Synthesis of(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128)

(2,3-Dichlorophenyl)boronic acid (225.6 mg, 1.182 mmol) and(S)-7-(5-amino-6-chloro-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(164.8 mg, 0.609 mmol) and cesium carbonate (701.2 mg, 2.131 mmol) weredissolved in water/dioxane (5/15 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (115.9 mg, 0.100 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 4 h. The mixture was concentrated to removeorganic solvents. The residue was dissolved in dichloromethane (30 mL).Water (10 mL) was added and brine (40 mL) was added. The organicsolution was separated and the aqueous solution was extracted withdichloromethane (2×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel to afford slight yellow solid(104.8 mg) as product in 45% yield. ¹H NMR (500 MHz, Chloroform-d) δ7.58 (dd, J=5.7, 3.9 Hz, 1H), 7.38-7.31 (m, 2H), 5.08 (d, J=12.5 Hz,1H), 4.86 (d, J=13.6 Hz, 1H), 4.79 (s, 2H), 4.47 (t, J=8.6 Hz, 1H), 4.02(dd, J=9.0, 5.6 Hz, 1H), 3.96-3.85 (m, 2H), 3.12 (td, J=12.7, 3.7 Hz,1H), 2.98 (td, J=12.8, 3.7 Hz, 1H), 2.85 (dd, J=13.0, 11.0 Hz, 1H). MSfor C₁₅H₁₄Cl₂N₆O₂: 381.0 (MH⁺).

(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (77.6 mg, 0.204 mmol) was dissolved in a mixture ofmethanol, acetonitrile and dichloromethane to afford a clear solution.2.0 M HCl in ether (0.6 mL, 1.2 mmol) was added. The mixture wasconcentrated to remove all of solvents to afford product as HCl salt(78.7 mg) in 93% yield. MS for C₁₅H₁₄Cl₂N₆O₂: 381.0 (MH⁺).

Example 76 Preparation of Compound 129 Synthesis of3-N-(3-hydroxyazetin-1-yl) lamotrigine Synthesis of1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-ol

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (87 mg, 5.28mmol), triethylamine (2.6 mL, 18.65 mmol), 3-hydroxyazetidinehydrochloride (656.3 mg, 5.81 mmol) in dioxane (10 mL). The mixture washeated at 90° C. for 1.5 h using microwave, 120° C. for 1 h. The mixturewas mixed with water. Aqueous sodium bicarbonate solution was addeduntil the solution is basic. Dichloromethane was added and sonicated fora few minutes. The mixture was filtered and the solid was washed withacetone, ether and dried under high vacuum to afford product (624 mg) in59% yield. ¹H NMR (500 MHz, Methanol-d₄) δ 4.64 (tt, J=6.7, 4.4 Hz, 1H),4.29 (ddd, J=9.7, 6.6, 1.2 Hz, 2H), 3.86 (ddd, J=9.6, 4.4, 1.2 Hz, 2H).

Synthesis of 3-N-(3-hydroxyazetin-1-yl) lamotrigine (Compound 129)

(2,3-Dichlorophenyl)boronic acid (0.934 g, 4.89 mmol),1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-ol (457.7 mg, 2.27mmol) and cesium carbonate (2.2244 g, 6.76 mmol) was dissolved inwater/dioxane (5/15 mL). The mixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (315.1 mg, 0.273 mmol) was added.The mixture was purged with nitrogen for a few minutes, and stirred at90° C. for 5 h. The mixture was concentrated to remove organic solvents.The residue was mixed with a mixture of dichloromethane and water,sonicated for a few minutes. The mixture was filtered and the solid waswashed with dichloromethane and dried under high vacuum to affordproduct (560.0 mg) in 79% yield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.67(dd, J=8.1, 1.6 Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 7.36 (dd, J=7.7, 1.6Hz, 1H), 4.69 (tt, J=6.6, 4.4 Hz, 1H), 4.37 (ddd, J=9.5, 6.6, 1.2 Hz,21H), 3.94 (ddd, J=9.5, 4.4, 1.2 Hz, 2H). MS for C₁₂H₁₁Cl₂N₅O: 312.0(MH⁺).

To a suspension of 3-N-(3-hydroxyazetin-1-yl) lamotrigine (46.9 mg,0.150 mmol) in methanol (6 mL), acetonitrile (3 mL), acetone (3 mL) wasadded 2.0 M HCl in ether (0.4 mL, 0.8 mmol). The mixture wasconcentrated to remove all of solvents to afford product as HCl salt. ¹HNMR (500 MHz, Methanol-d₄) δ 9.07 (s, 1H), 8.19 (s, 1H), 7.77 (dd,J=7.9, 1.7 Hz, 1H), 7.52-7.42 (m, 2H), 4.78 (tt, J=6.7, 4.3 Hz, 1H),4.53 (ddd, J=10.1, 6.7, 1.4 Hz, 2H), 4.08 (ddd, J=10.1, 4.3, 1.4 Hz,2H). MS for C₁₂H₁₁Cl₂N₅O: 312.0 (MH⁺).

Example 77 Preparation of Compound 130 Synthesis of(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130) Synthesis of(R)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (331 mg,2.006 mmol), triethylamine (1.8 mL, 12.91 mmol),(R)-hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one Hexahydrochloride(465.5 mg, 2.102 mmol) in dioxane (10 mL). The mixture was heated at 120degree for 1.5 h using microwave. The mixture was concentrated to removeall of solvent. The residue was dissolved in dichloromethane, washedwith aqueous sodium bicarbonate solution. The aqueous solution wasextracted with dichloromethane (2×30 mL). The combined organic solutionwas washed with brine, dried over anhydrous sodium sulfate,concentrated. The residue was mixed with small amount ofdichloromethane, warmed up and cooled to r.t. The mixture was filteredand the solid was washed with small amount of dichloromethane. The solidwas collected and dried under high vacuum (242.8 mg). The solution wascollected and purified with flash column chromatography on silica gelusing 1-5% methanol in dichloromethane to afford another part of product(179.6 mg). The total yield was 74%. ¹H NMR (500 MHz, Chloroform-d) δ5.29 (s, 2H), 4.74-4.60 (m, 3H), 4.24-4.12 (m, 2H), 4.04 (q, J=8.0 Hz,1H), 3.65-3.55 (m, 2H), 2.96 (ddd, J=13.8, 12.2, 3.6 Hz, 1H), 2.85-2.71(m, 2H). MS for C₁₀H₁₃ClN₆O₂: 285.0 (MH⁺).

Synthesis of(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130)

(2,3-Dichlorophenyl)boronic acid (0.3392 g, 1.778 mmol),(R)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one(244.1 mg, 0.857 mmol) and cesium carbonate (0.8478 g, 2.58 mmol) wasdissolved in water/dioxane (5/1.5 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (158.4 mg, 0.137 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 5 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using 30-100% ethyl acetate inhexane to afford yellow solid as product (290.1 mg) in 86% yield. ¹H NMR(500 MHz, Chloroform-d) δ 7.57 (dd, J=6.3, 3.3 Hz, 1H), 7.35 (q, J=3.8,3.2 Hz, 2H), 4.90-4.82 (m, 2H), 4.79 (s, 2H), 4.71-4.64 (m, 1H),4.24-4.16 (m, 2H), 4.12-4.02 (m, 2H), 3.70-3.58 (m, 2H), 3.01 (td,J=12.9, 3.4 Hz, 1H), 2.89-2.77 (m, 2H). MS for C₁₆H₁₆Cl₂N₆O₂: 395.0(MH⁺).

To a solution of(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydro-pyrazino[2,1-c][1,4]oxazin-4(3H)-one(62.1 mg, 0.157 mmol) in methanol (3 mL) was added 2.0 M HCl in ether(0.4 mL, 0.8 mmol). The mixture was concentrated to remove all ofsolvents to afford product as HCl salt (57.2 mg, white solid, yield:84%). ¹H NMR (500 MHz, Methanol-d₄) δ 7.79 (dd, J=7.9, 1.8 Hz, 1H),7.55-7.44 (m, 2H), 4.58 (dt, J=13.5, 3.4 Hz, 1H), 4.41 (br, 2H), 4.20(s, 2H), 4.11 (dd, J=12.2, 4.5 Hz, 1H), 3.92-3.82 (m, 1H), 3.81-3.71 (m,1H), 3.45-3.37 (m, 1H), 3.28-3.30 (m, 1H), 3.08 (ddd, J=14.5, 11.4, 3.6Hz, 1H).

Example 78 Preparation of Compound 131 Synthesis of(S)-6-(2,3-dichlorophenyl)-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1,2,4-triazin-5-aminedi HCl salt (Compound 131) Synthesis of(R)-8-(5-amino-6-chloro-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (358.7 mg,2.174 mmol), triethylamine (1.8 mL, 12.91 mmol),(S)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (504.1 mg,2.296 mmol) in dioxane (10 mL). The mixture was heated at 120° C. for1.5 h using microwave. The mixture was concentrated to remove all ofsolvent. The residue was dissolved in dichloromethane, washed withaqueous sodium bicarbonate solution. The aqueous solution was extractedwith dichloromethane (2×30 mL). The combined organic solution was washedwith brine, dried over anhydrous sodium sulfate, concentrated. Theresidue was purified with flash column chromatography on silica gelusing 1-5% methanol in dichloromethane to afford slightly pink solid(0.5041 g) in 86% yield. ¹H NMR (500 MHz, Chloroform-d) δ 5.20 (s, 2H),4.60 (d, J=13.3 Hz, 1H), 4.44 (d, J=12.8 Hz, 1H), 3.85 (dd, J=11.4, 3.3Hz, 1H), 3.76 (dd, J=11.1, 3.1 Hz, 1H), 3.71 (t, J=11.5 Hz, 1H), 3.28(t, J=10.6 Hz, 1H), 3.08 (t, J=12.4 Hz, 1H), 2.79 (d, J=11.4 Hz, 1H),2.68 (d, J=11.6 Hz, 1H), 2.57 (t, J=12.0 Hz, 1H), 2.38 (t, J=11.0 Hz,1H), 2.28 (t, J=12.4 Hz, 1H), 2.23 (s, 1H). MS for C₁₀H₁₅ClN₆O: 271.0(MH⁺).

Synthesis of(S)-6-(2,3-dichlorophenyl)-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1,2,4-triazin-5-aminedi HCl salt (Compound 131)

(2,3-Dichlorophenyl)boronic acid (0.450.4 g, 2.360 mmol),(S)-6-chloro-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1,2,4-triazin-5-amine(282.3 mg, 1.043 mmol) and cesium carbonate (1.1547 g, 3.51 mmol) wasdissolved in water/dioxane (5/15 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (178.5 mg, 0.154 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 4 h 45 min. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using 30-100% ethyl acetate inhexane and 10% methanol in ethyl acetate to afford a yellow solid (376.8mg) in 95% yield. ¹H NMR (500 MHz, Chloroform-d) 7.55 (dd, J=7.4, 2.3Hz, 1H), 7.38-7.29 (m, 2H), 4.77 (s, 1H), 4.72 (s, 2H), 4.59 (d, J=12.6Hz, 1H), 3.87 (dd, J=11.4, 3.3 Hz, 1H), 3.79 (dd, J=11.1, 3.1 Hz, 1H),3.73 (td, J=11.5, 2.4 Hz, 1H), 3.32 (t, J=11.1, 10.2 Hz, 1H), 3.14 (td,J=12.7, 3.2 Hz, 1H), 2.87-2.80 (m, 1H), 2.71 (d, J=11.7 Hz, 1H), 2.63(dd, J=12.8, 10.9 Hz, 1H), 2.46-2.23 (m, 3H). MS for C₁₆H₁₈Cl₂N₆O: 381.0(MH⁺).

To a solution of(S)-6-(2,3-dichlorophenyl)-3-(hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl)-1,2,4-triazin-5-amine(76.1 mg, 0.20 mmol) in methanol (3 mL) was added 2.0 M HCl in ether(0.4 mL, 0.8 mmol). The mixture was concentrated to remove all ofsolvents to afford product as HCl salt (73.5 mg, white solid) in 94%yield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.80 (dd, J=7.9, 1.8 Hz, 1H),7.53-7.47 (m, 2H), 4.63 (br, 2H), 4.10 (d, J=12.4 Hz, 2H), 4.01 (t,J=12.6 Hz, 2H), 3.77-3.64 (m, 4H), 3.57-3.52 (s, 1H), 3.46-3.37 (m, 2H).

Example 79 Preparation of Compound 132 Synthesis of 3-N-(azetidin-3-yl)lamatrogine 2HCl salt (Compound 132) Synthesis of5-amino-3-(1-Boc-azetidin-3-yl)amino-6-chloro-1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (899.5 mg,5.45 mmol), diisopropylethylamine (2.0 mL, 11.48 mmol), 3-amino-1-N-Bocazetidine (1.1452 g, 6.45 mmol) in dioxane (15 mL). The mixture washeated at 120° C. for 3 h using microwave. More of diisopropylethylamine(0.5 mL) and 3-amino-1-N-Boc azetidine (256 mg) were added. The mixturewas heated at 120° C. for another 2 h. The mixture was concentrated toremove all of solvent. The residue was dissolved in dichloromethane,washed with aq. sodium bicarbonate solution. The organic solution wasseparated. The aqueous solution was mixed with brine, extracted withdichloromethane (2×35 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated to afford a residue. The residuewas mixed with small amount of dichloromethane, warmed up and cooleddown to room temperature. The mixture was filtered and the solid waswashed with dichloromethane and ether. The solid was collected and driedto afford first batch of product (897.1 mg). The solution wasconcentrated to remove all of solvents. The residue was purified withflash column chromatography on silica gel using 1-5% methanol indichloromethane (266.8 mg). The total yield was 71%. ¹H NMR (500 MHz,Chloroform-d) δ 5.28 (br, 2H), 4.60 (s, 1H), 4.31-4.23 (t, J=9.0 Hz,2H), 3.77 (dd, J=9.4, 5.2 Hz, 2H), 1.43 (s, 9H). MS for C₁₁H₁₇ClN₆O₂:301.0 (MH⁺).

Synthesis of 3-N-(1-Boc-azetidin-3-yl) lamotrigine

(2,3-Dichlorophenyl)boronic acid (231.4 mg, 1.213 mmol),5-amino-3-(1-Boc-azetidin-3-yl)amino-6-chloro-1,2,4-triazine (173 mg,0.575 mmol) and cesium carbonate (579.5 mg, 1.761 mmol) was dissolved inwater/dioxane (5/15 mL). The mixture was degassed with nitrogen,tetrakis(triphenylphosphine)palladium (117 mg, 0.101 mmol) was added.The mixture was purged with nitrogen for a few minutes, and stirred at90° C. for 6 h. The mixture was concentrated to remove organic solvents.The residue was mixed with brine, extracted with dichloromethane (3×50mL). The combined organic solution was dried over anhydrous sodiumsulfate, concentrated. The residue was purified twice with flash columnchromatography on silica gel using 30-100% ethyl acetate/hexane and30-60% acetone/hexane to afford product as yellowish solid (94.9 mg) in40% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J=6.7, 3.0 Hz,1H), 7.36-7.31 (m, 2H), 4.81 (s, 2H), 4.70 (s, 1H), 4.29 (t, J=8.4 Hz,2H), 3.84 (dd, J=9.2, 5.2 Hz, 2H), 1.42 (s, 9H). MS for C₁₇H₂₀Cl₂N₆O₂:411.0 (MH⁺).

Synthesis of 3-N-(azetidin-3-yl) lamatrogine 2HCl salt (Compound 132)

3-N-(1-Boc-azetidin-3-yl) lamotrigine (94.9 mg, 0.231 mmol) wasdissolved in methanol (1 mL). 4 N HCl in dioxane (0.5 mL) at roomtemperature was added. The solution was stirred at room temperature for5 h. The mixture was concentrated to remove all of solvent to affordproduct as HCl salt (62.2 mg) in 94% yield. ¹H NMR (500 MHz,Methanol-d₄) δ 7.79 (dd, J=7.9, 1.7 Hz, 1H), 7.55-7.44 (m, 2H),5.02-4.89 (m, 1H), 4.45-4.41 (m, 2H), 4.39-4.35 (m, 2H). MS forC₁₂H₁₂Cl₂N₆: 311.0 (MH⁺).

Example 80-A Preparation of Compound 165 Synthesis of3-N-(3-hydroxy-3-trifluoromethyl)azetidinyl lamotrigine (Compound 165)Synthesis of5-amino-6-chloro-3-N-(3-Hydroxy-3-trifluoromethyl)azetidinyl1,2,4-triazine

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (290.27 mg,1.759 mmol), diisopropylethylamine (1.5 mL, 8.61 mmol),3-(trifluoromethyl)azetidin-3-ol HCl salt (371.5 mg, 2.093 mmol) indioxane (3 mL). The mixture was heated at 120° C. for 30 min usingmicrowave. The mixture was concentrated to remove all of solvents. Theresidue was dissolved in dichloromethane, washed with aqueous sodiumbicarbonate solution. Some brine was added. The organic solution wasseparated. The organic mixture was filtered and washed withdichloromethane to collect the white solid as product. The aqueoussolution was saturated with sodium chloride, extracted withdichloromethane. The combined organic solution was concentrated toafford a residue. The residue was dissolved into a small of amount ofwarm dichloromethane, cooled. The solid was collected and washed withdichloromethane to afford second batch of product. The total yield wasquantitative. ¹H NMR (500 MHz, Methanol-d₄) δ 4.30 (d, J=10.0 Hz, 2H),4.02 (d, J=10.1 Hz, 2H). MS for C₇H₇ClF₃N₅O: 270.0 (MH⁺).

Synthesis of 3-N-(3-hydroxy-3-trifluoromethyl)azetidinyl lamotrigine(Compound 165)

(2,3-Dichlorophenyl)boronic acid (249.8 mg, 1.309 mmol),1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(trifluoromethyl)azetidin-3-ol(200.8 mg, 0.745 mmol) and cesium carbonate (782.8 mg, 2.379 mmol) wasdissolved in water/dioxane (5/15 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (148.3 mg, 0.128 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 2.5 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified twicewith flash column chromatography on silica gel using 1-10% methanol indichloromethane. The product was mixed with small amount ofdichloromethane, warmed up, cooled and filtrated. The solid wascollected to afford the final product (98.6 mg) in 35% yield. ¹H NMR(500 MHz, Methanol-d₄) δ 7.68 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (t, J=7.8Hz, 1H), 7.37 (dd, J=7.6, 1.5 Hz, 1H), 4.38 (d, J=10.1 Hz, 2H), 4.10 (d,J=10.1 Hz, 2H). MS for C₁₃H₁₀Cl₂F₃N₅O: 380.0 (MH⁺).

62.4 mg of free base was dissolved into methanol (0.5 mL), added 4N HClin dioxane (1 mL) was added. The mixture was stirred for a few minutesand then concentrated to dryness to afford the product as HCl salt. ¹HNMR (500 MHz, Methanol-d₄) δ 7.78 (dd, J=7.9, 1.7 Hz, 1H), 7.54-7.43 (m,2H), 4.57 (d, J=1.0.5 Hz, 2H), 4.30 (d, J=1.0.6 Hz, 2H).

Example 80-B Preparation of Compound 133 Synthesis of3-N-(4-hydroxy-4-trifluoromethyl)piperidinyl lamotrigine (Compound 133)Synthesis of1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-(trifluoromethyl)piperidin-4-ol

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (203.4 mg,1.233 mmol), diisopropylethylamine (1.5 mL, 8.61 mmol),4-(trifluoromethyl)piperidin-4-ol HCl (268.6 mg, 1.306 mmol) in dioxane(3 mL). The mixture was heated at 120° C. for 65 min using microwave.The mixture was concentrated to remove all of solvent. The residue wasdissolved in dichloromethane, washed with aqueous sodium bicarbonatesolution. The organic solution was separated. The aqueous solution wasmixed with brine, extracted with dichloromethane (2×35 mL). The combinedorganic solution was dried over anhydrous sodium sulfate, concentratedto afford a residue. The residue was purified with flash columnchromatography on silica using 1-10% methanol in dichloromethane (273.4mg) in 75% yield. ¹H NMR (500 MHz, Chloroform-d) δ 4.57 (d, J=13.5 Hz,2H), 3.35 (s, 1H), 3.21-3.15 (m, 2H), 1.77-1.74 (m, 2H). MS forC₉H₁₁ClF₃N₅O: 298.0 (MH⁺).

Synthesis of 3-N-(4-hydroxy-4-trifluoromethyl)piperidinyl lamotrigine(Compound 133)

(2,3-Dichlorophenyl)boronic acid (228.6 mg, 1.198 mmol),1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4-(trifluoromethyl)piperidin-4-ol(224 mg, 0.753 mmol) and cesium carbonate (725.3 mg, 2.204 mmol) wasdissolved in water/dioxane (5/15 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (127.5 mg, 0.110 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 2 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified twicewith flash column chromatography on silica gel using 30-100% ethylacetate/hexane. The product was dissolved in warm dichloromethane,cooled, filtered. The white solid was collected to afford product (161.7mg) in 53% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.55 (dd, J=7.6, 2.0Hz, 1H), 7.38-7.26 (m, 2H), 4.82 (d, J=13.4 Hz, 2H), 4.71 (s, 2H), 3.24(td, J=13.1, 2.8 Hz, 2H), 1.96 (s, 1H), 1.89 (td, J=13.1, 4.6 Hz, 21-H),1.80 (d, J=2.5 Hz, 1H), 1.77 (s, 1H). MS for C₁₅H₁₄Cl₂F₃N₅O: 408.1(MH⁺).

112.6 mg of free base was dissolved in methanol (2 mL), 4 N HCl indioxane (1 mL) was added. The mixture was stirred for a few minutes, andthen concentrated to dryness and dried under high vacuum to affordproduct as HCl salt. ¹H NMR (500 MHz, Methanol-d₄) δ 7.68 (dd, J=7.8,1.7 Hz, 1H), 7.44-7.34 (m, 2H), 4.34 (br, 2H), 3.56 (s, 6H), 3.40 (m,2H), 1.92-1.78 (m, 4H). MS for C₁₅H₁₄Cl₂F₃N₅O: 408.1 (MH⁺).

Example 81 Preparation of Compound 134 Synthesis of(S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 134) Synthesis of (S)-tert-butyl4-((S)-2-hydroxy-3-methoxypropyl)-3-(hydroxymethyl)piperazine-1-carboxylate

A vial was charged with (S)-tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (321.4 mg, 1.441 mmol) and(S)-2-(methoxymethyl)oxirane (162.4 mg, 1.788 mmol) in ethanol (2.5 mL).The mixture was heated at 120° C. for 30 min using microwave. Themixture was cooled to room temperature, concentrated to remove all ofsolvent. The residue was purified with flash column chromatography onsilica gel using 1-10% methanol in dichloromethane to afford the finalproduct as colorless oil (379.3 mg) in 86% yield. ¹H NMR (500 MHz,Chloroform-d) δ 3.88 (m, 1H), 3.82 (m, 1H), 3.66 (dd, J=13, 3 Hz, 1H),3.64 (br, 1H), 3.50-3.47 (m, 2H), 3.41 (dd, J=9.7, 3.8 Hz, 1H), 3.37 (s,3H), 3.30 (dd, J=9.7, 6.2 Hz, 1H), 3.25 (br, 1H), 2.90 (br, 1H), 2.80(t, J=11.5 Hz, 2H), 2.46 (br, 1H), 2.35 (m, 2H), 1.43 (s, 9H). MS forC₁₄H₂₈N₂O₅: 305.2 (MH⁺).

Synthesis of(S)-1-((S)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol 2HClsalt

(S)-Tert-butyl4-((S)-2-hydroxy-3-methoxypropyl)-3-(hydroxymethyl)piperazine-1-carboxylate(0.3793 g, 1.245 mmol) was dissolved in ethanol (4 mL). 4 N HCl indioxane (1.5 mL) was added. The mixture was stirred at room temperaturefor 1 h. More of 4 N HCl in dioxane (1.5 mL) was added. The mixture wasstirred at r.t. for 3 h. The mixture was concentrated to remove thesolvents. The residue was dried under high vacuum to afford white solidin quantitative yield. ¹H NMR (500 MHz, Methanol-d₄) δ 4.24 (dq, J=9.6,4.9 Hz, 1H), 4.13 (dd, J=12.9, 3.5 Hz, 1H), 3.97 (dt, J=14.1, 3.4 Hz,1H), 3.84 (d, J=10.6 Hz, 1H), 3.77-3.68 (m, 4H), 3.66 (s, 3H), 3.62-3.49(s, 4H), 3.45-3.42 (m, 2H), 3.40 (s, 3H).

Synthesis of(S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol

A mixture of 5-amino-3,6-dichloro-1,2,4-triazine (191.7 mg, 1.38 mmol),diisopropylethylamine (2.5 mL, 14.35 mmol), (S)-tert-butyl2-(3-(hydroxymethyl)piperazin-1-yl)acetate diHCl (˜344 mg, 1.24 mmol) indioxane (10 mL) was heated at 95° C. for 2 h 20 min. The mixture wasconcentrated to remove all of solvents. The residue was dissolved indichloromethane, washed with aqueous sodium bicarbonate solution. Theorganic solution was separated. The aqueous solution was mixed withbrine, extracted with dichloromethane (2×35 mL). The combined organicsolution was dried over anhydrous sodium sulfate, concentrated to afforda residue. The residue was purified with flash column chromatography onsilica using 1-10% methanol in dichloromethane to afford product (69.5mg) in 18% yield. MS for C₁₂H₂₁ClN₆O₃: 330 (MH⁺).

Synthesis of(S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 134)

(2,3-Dichlorophenyl)boronic acid (94.6 mg, 0.496 mmol),(S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(69 mg, 0.207 mmol) and cesium carbonate (231.1 mg, 0.702 mmol) wasdissolved in water/dioxane (3/10 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (72.2 mg, 0.062 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 17.5 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using methanol indichloromethane to afford product (54.9 mg) in 60% yield. ¹H NMR (500MHz, Chloroform-d) 7.53 (dd, J=7.5, 2.1 Hz, 1H), 7.36-7.26 (m, 2H), 4.94(br, 2H), 4.17 (d, J=11.4 Hz, 2H), 3.92 (ddt, J=9.6, 6.7, 3.6 Hz, 1H),3.81 (dd, J=11.9, 5.6 Hz, 1H), 3.69-3.50 (m, 3H), 3.41 (dd, J=9.9, 4.1Hz, 1H), 3.35 (s, 3H), 3.34-3.31 (m, 1H), 3.05-2.97 (m, 1H), 2.81 (dd,J=13.5, 9.6 Hz, 1H), 2.62 (br, 1H), 2.52-2.41 (m, 2H). MS forC₁₈H₂₄Cl₂N₆O₃: 443.0 (MH⁺).

41.6 mg of product was dissolved in methanol (˜2 mL), 4 N HCl in dioxane(1 mL) was added. The mixture was concentrated to remove all of solventsand dried under high vacuum to afford the HCl salt. ¹H NMR (500 MHz,Methanol-d₄) δ 7.80 (dd, J=7.9, 1.7 Hz, 2H), 7.55-7.45 (m, 2H), 4.57(br, 2H), 4.25 (s, 1H), 4.1.1 (d, J=11.5 Hz, 1H), 3.90 (m, 1H),3.84-3.79 (m, 2H), 3.77-3.71 (m, 2H), 3.68-3.66 (m, 5H), 3.61-3.57 (m,2H), 3.54-3.51 (m, 1H), 3.47-3.44 (m, 1H), 3.41 (s, 3H). MS forC₁₈H₂₄Cl₂N₆O₃: 443.0 (MH⁺).

Example 82 Preparation of Compound 135 Synthesis of(s)-5-N-(3-(hydroxymethyl)piperazinyl lamotrigine diHCl (Compound 135)Synthesis of (S)-tert-butyl4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (253.3 mg,1.535 mmol), diisopropylethylamine (2.0 mL, 11.48 mmol), (S)-tert-butyl2-(3-(hydroxymethyl)piperazin-1-yl)acetate (410.9 mg, 1.731 mmol) indioxane (2 mL). The mixture was heated at 120° C. for 5 h usingmicrowave. The mixture was concentrated to remove all of solvent. Theresidue was dissolved in dichloromethane, washed with aqueous sodiumbicarbonate solution. The organic solution was separated. The aqueoussolution was mixed with brine, extracted with dichloromethane (2×35 mL).The combined organic solution was dried over anhydrous sodium sulfate,concentrated to afford a residue. The residue was dissolved into smallamount of dichloromethane, filtered. The solid was collected the firstbatch of product. The solution was purified with flash columnchromatography on silica using 1-10% methanol in dichloromethane toafford another batch of product. The product was slight yellow solid(343 mg) and the yield was 65%. ¹H NMR (500 MHz, Chloroform-d) δ 5.26(br, 2H), 4.76 (s, 1H), 4.43 (d, J=13.3 Hz, 1H), 4.23-3.92 (s, 2H), 3.65(m, 2H), 3.16-2.90 (s, 4H), 1.47 (s, 9H). MS for C₁₃H₂₁ClN₆O₃: 345.0(MH⁺).

Synthesis of (s)-5-N-(4-N-t-Boc-3-(hydroxymethyl)piperazinyl lamotrigine

(2,3-Dichlorophenyl)boronic acid (187.1 mg, 0.981 mmol), (S)-tert-butyl4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate(156 mg, 0.452 mmol) and cesium carbonate (485.3 mg, 1.475 mmol) wasdissolved in water/dioxane (3/10 mL). The mixture was degassed withnitrogen, Tetrakis(triphenylphosphine)palladium (107.5 mg, 0.093 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 3 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified twicewith flash column chromatography on silica gel using 1-10% methanol indichloromethane to afford slight yellow solid as product (126.5 mg) in61% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J=6.6, 3.1 Hz,1H), 7.37-7.29 (m, 2H), 4.90 (br, 1H), 4.79 (s, 2H), 4.57 (br, 1H),4.23-3.98 (s, 2H), 3.73 (br, 2H), 3.24 (s, 2H), 3.09 (s, 2H), 1.48 (s,9H). MS for C₁₉H₂₄Cl₂N₆O₃: 455.0 (MH⁺).

Synthesis of (s)-5-N-(3-(hydroxymethyl)piperazinyl lamotrigine diHCl(Compound 135)

(S)-Tert-butyl4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (64.3 mg, 0.141 mmol) was dissolved in methanol(2 mL), 4N HCl in dioxane (0.75 mL, 3.0 mmol) was added. The mixture wasstirred at room temperature for 1 h 50 min. The mixture was concentratedto remove all of solvents to afford the product as HCl salt in whitepowder (53 mg) in 88% yield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.80 (dd,J=7.8, 1.9 Hz, 1H), 7.55-7.46 (m, 2H), 4.62 (br, 1H), 4.09 (m, 1H), 4.01(dd, J=11.2, 4.1 Hz, 1H), 3.85 (br, 1H), 3.77-3.73 (m, 1H), 3.68-3.65(m, 1H), 3.60-3.57 (m, 1H), 3.50-3.45 (m, 1H), 3.35 (m, 1H). MS forC₁₄H₁₆Cl₂N₆O: 355.0 (MH⁺).

Example 83 Preparation of Compound 136 Synthesis of1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(Compound 136) Synthesis of (3 S)-tert-butyl4-(3-(tert-butoxy)-2-hydroxypropyl)-3-(hydroxymethyl)piperazine-1-carboxylate

A vial was charged with (S)-tert-butyl3-(hydroxymethyl)piperazine-1-carboxylate (367.3 mg, 1.647 mmol) and2-(tert-butoxymethyl)oxirane (243.3 mg, 1.850 mmol) in ethanol (3 mL).The mixture was heated at 120° C. for 30 min using microwave. Themixture was cooled to room temperature, concentrated to remove all ofsolvents. The residue was purified with flash column chromatography onsilica gel using 1-10% methanol in dichloromethane to afford the finalproduct as colorless oil (497.5 mg) in 87% yield. ¹H NMR (500 MHz,Chloroform-d) δ 3.86-3.80 (m, 2H), 3.71-3.68 (m, 1H), 3.53-3.41 (m, 2H),3.40-3.35 (m, 2H), 3.24 (dd, J=9.1, 6.6 Hz, 1H), 3.10 (br, 1H), 2.91 (m,1H), 2.83-2.75 (m, 1H), 2.48 (dd, J=13.1, 7.6 Hz, 2H), 2.39-2.30 (m,1H), 1.44 (s, 9H), 1.18, 1.17 (2s, 9H). MS for C₁₇H₃₄N₂O₅: 347.2 (MH⁺).

Synthesis of1-(tert-butoxy)-3-((S)-2-(hydroxymethyl)piperazin-1-yl)propan-2-ol diHCl salt

(3S)-Tert-butyl4-(3-(tert-butoxy)-2-hydroxypropyl)-3-(hydroxymethyl)piperazine-1-carboxylate(0.4975 g, 1.434 mmol) was dissolved in ethanol (2.5 mL). 4 N HCl indioxane (3 mL) was added. The mixture was stirred at r.t. for 2 h. Themixture was concentrated to remove all of solvents. The residue wasdried under high vacuum for overnight to afford product quantitativeyield. ¹H NMR (500 MHz, Methanol-d₄) δ 4.20-4.12 (m, 2H), 4.08-3.92 (m,2H), 3.88-3.82 (m, 1H), 3.78-3.61 (m, 9H), 3.58-3.45 (m, 5H), 3.41-3.36(m, 1H), 1.23 (s, 9H). MS for C₁₂H₂₆N₂O₃: 247.2 (MH⁺).

Synthesis of1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol

A mixture of 5-amino-3,6-dichloro-1,2,4-triazine (226.7 mg, 1.374 mmol),diisopropyl-ethylamine (2.5 mL, 14.35 mmol),1-(tert-butoxy)-3-((S)-2-(hydroxymethyl)piperazin-1-yl)propan-2-ol 2HCl(˜349 mg, 1.43 mmol) in dioxane (10 mL) was heated at 90° C. for 3.5 h.The mixture was concentrated to remove all of solvents. The residue wasdissolved in dichloromethane, washed with aqueous sodium bicarbonatesolution. The organic solution was separated. The aqueous solution wasmixed with brine, extracted with dichloromethane (2×35 mL). The combinedorganic solution was dried over anhydrous sodium sulfate, concentratedto afford a residue. The residue was purified with flash columnchromatography on silica using 1-10% methanol in dichloromethane toafford product in quantitative yield. ¹H NMR (500 MHz, Chloroform-d) δ5.26 (m, 2H), 4.15 (d, J=12.1 Hz, 1H), 3.85 (m, 3H), 3.78-3.70 (m, 1H),3.65-3.53 (m, 2H), 3.46-3.52 (m, 2H), 3.28-3.25 (m, 1H), 3.00 (m, 1H),2.87-2.73 (m, 2H), 2.61-2.37 (m, 3H), 1.18, 1.17 (2s, 9H). MS forC₁₅H₂₇ClN₆O₃: 375.2 (MH⁺).

Synthesis of1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxy-ethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(Compound 136)

(2,3-Dichlorophenyl)boronic acid (218.7 mg, 1.146 mmol),1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(229.5 mg, 0.612 mmol) and cesium carbonate (596.5 mg, 1.812 mmol) wasdissolved in water/dioxane (3/10 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (138.7 mg, 0.120 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 5 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified twicewith flash column chromatography on silica gel using 30-100% ethylacetate in hexane. The product was dissolved in warm dichloromethane,cooled, filtered. The solution was collected and purified with flashcolumn chromatography on silica gel using 1-10% methanol indichloromethane to afford the product yellow solid (12 mg) in 41%. ¹HNMR (500 MHz, Chloroform-d) δ 7.56-7.54 (m, 1H), 7.36-7.31 (m, 2H), 4.74(d, J=11.6 Hz, 2H), 4.24 (d, J=13.7 Hz, 1H), 3.94-3.77 (m, 4H),3.61-3.52 (m, 2H), 3.45-3.38 (m, 2H), 3.28 (dd, J=9.0, 6.6 Hz, 1H), 3.03(d, J=11.7 Hz, 1H), 2.87-2.77 (m, 2H), 2.64-2.62 (m, 1H), 2.56-2.50 (m,1H), 2.41 (d, J=13.7 Hz, 1H), 1.18, 1.19 (2s, 9H). MS for C₂₁H₃₀Cl₂N₆O₃:485.2 (MH⁺).

Example 84 Preparation of Compound 137 Synthesis of3-N-[(4-N-2,3-di-hydroxy-propanyl)-(s)-3-hydroxymethyl)]piperazinyl-lamotrigine di HCl salt (Compound 137)

1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol (63.8 mg, 0.131 mmol) wasdissolved into methanol (2 mL), 4 N HCl in dioxane (4 mL) was added. Themixture was stirred at room temperature until LC-MS showed the reactioncompleted. The mixture was concentrated to remove the solvents. Theresidue was dried under high vacuum to afford the product as HCl salt inquantitative yield (slight yellow foam). ¹H NMR (500 MHz, Methanol-d₄) δ7.80 (dd, J=7.8, 1.8 Hz, 1H), 7.54-7.48 (m, 2H), 4.57 (br, 2H),4.23-4.12 (m, 2H), 4.0 (br, 1H), 3.93-3.90 (m, 1H), 3.88-3.82 (m, 3H),3.77-3.73 (m, 2H), 3.68-3.63 (m, 6H), 3.61-3.58 (m, 3H), 3.56-3.50 (m,1H).). MS for C₁₇H₂₂Cl₂N₆O₃: 429.0 (MH⁺).

Example 85 Preparation of Compound 138 Synthesis of(S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 138) Synthesis of (S)-tert-butyl4-((S)-2-hydroxy-3-methoxypropyl)-2-(hydroxymethyl)piperazine-1-carboxylate

A mixture of (S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate(602.7 mg, 2.79 mmol) and (S)-2-methoxyoxirane (308.9 mg, 3.4 mmol) inethanol (10 mL) was heated at 120° C. for 30 min using microwave. Themixture was concentrated to dryness. The residue was purified with flashcolumn chromatography on silica gel using 1-10% methanol indichloromethane to afford a oil as the product (794.6 mg) in 94% yield.¹H NMR (500 MHz, Chloroform-d) δ 4.11 (br, 1H), 3.93-3.80 (m, 2H), 3.41(dd, 0.1=9.7, 3.7 Hz, 1H), 3.36 (s, 3H), 3.33 (dd, J=9.7, 6.0 Hz, 1H),3.25 (br, 2H), 3.06 (d, J=11.6 Hz, 1H), 2.89 (br, 2H), 2.79 (d, J=11.2Hz, 1H), 2.47 (dd, J=12.7, 9.1 Hz, 1H), 2.49-2.33 (m, 1H), 2.30-2.21 (m,2H), 1.43 (s, 9H). MS for C₁₄H₂₈N₂O₅: 305.2 (MH⁺).

Synthesis of(S)-1-((S)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol 2HClsalt

(S)-Tert-butyl4-((S)-2-hydroxy-3-methoxypropyl)-2-(hydroxymethyl)piperazine-1-carboxylate(794 mg, 2.61 mmol) was dissolved in ethanol (6 mL), 4 N HCl in dioxane(2.9 mL) was added. The mixture was stirred at room temperature for 4.5h. More of 4 N HCl in dioxane (1 mL) was added. The mixture was stirredat room temperature for 18 h. The mixture was concentrated to remove allof solvents to afford white solid as product in 98% yield. ¹H NMR (500MHz, Methanol-d₄) δ 4.26 (br, 1H), 3.97-3.82 (m, 2H), 3.78-3.71 (m, 2H),3.66 (s, 1H), 3.61-3.54 (m, 2H), 3.52-3.41 (m, 4H), 3.39 (s, 3H),3.37-3.33 (m, 1H).

Synthesisof(S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol

A mixture of 5-amino-3,6-dichloro-1,2,4-triazine (250.2 mg, 1.517 mmol),diisopropylethylamine (2.0 mL, 11.48 mmol),(S)-1-((S)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol 2HCl(˜500 mg, 1.804 mmol) in dioxane (7 mL) was heated at 150° C. for 4 h.The mixture was concentrated to remove all of solvents. The residue wasdissolved in dichloromethane, washed with aq. sodium bicarbonatesolution. The organic solution was separated. The aqueous solution wassaturated with sodium chloride, extracted with dichloromethane (2×35mL). The combined organic solution was dried over anhydrous sodiumsulfate, concentrated to afford a residue. The residue was purified withflash column chromatography on silica using 1-10% methanol indichloromethane to afford product (169.9 mg) in 37% yield. 1H NMR (500MHz, Methanol-d₄) δ 4.62 (br, 1H), 4.38 (d, J=13.1 Hz, 1H), 3.97-3.88(m, 2H), 3.70 (dd, J=10.5, 5.6 Hz, 1H), 3.46 (dd, J=9.9, 4.1 Hz, 1H),3.42-3.33 (m, 1H), 3.37 (s, 3H), 3.19 (br, 2H), 2.95 (d, J=11.2 Hz, 1H),2.43 (br, 2H), 2.21 (d, J=10.9 Hz, 2H). MS for C₁₂H₂₁ClN₆O₃: 354.2(MH⁺).

Synthesis of(S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 138)

(2,3-Dichlorophenyl)boronic acid (162.5 mg, 0.852 mmol),(S)-1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(156.4 mg, 0.470 mmol) and cesium carbonate (485.4 mg, 1.475 mmol) wasdissolved in water/dioxane (3/10 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (100.8 mg, 0.087 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 3 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×50 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified twicewith flash column chromatography on silica gel using 30-100% ethylacetate/hexane. The product was dissolved in warm dichloromethane,cooled, filtered. The solution was collect and purified with flashcolumn chromatography on silica gel using 1-10% methanol indichloromethane to afford the product (141.5 mg) in 68% yield. ¹H NMR(500 MHz, Chloroform-d) δ 7.56 (dd, J=7.3, 2.3 Hz, 1H), 7.39-7.29 (m,2H), 4.91 (br, 1H), 4.75 (s, 2H), 4.63 (br, 1H), 4.04-3.92 (m, 3H),3.47-3.42 (m, 3H), 3.39 (s, 3H), 3.40-3.36 (m, 1H), 3.19 (d, J=11.7 Hz,1H), 3.07 (br, 1H), 2.94 (d, J=11.4 Hz, 1H), 2.52 (dd, J=12.6, 9.0 Hz,1H), 2.42-2.32 (m, 3H). MS for C₁₈H₂₄Cl₂N₆O₃: 443.0 (MH⁺).

54.1 mg of product was dissolved in methanol (˜1 mL), 4 N HCl in dioxane(1 mL) was added. The mixture was concentrated to remove all of solventsand dried under high vacuum to product as HCl salt in quantitativeyield. ¹H NMR (500 MHz, Methanol-d₄) δ 7.80 (dd, J=7.7, 2.0 Hz, 1H),7.56-7.46 (m, 2H), 4.27 (m, 1H), 4.17-4.09 (m, 1H), 3.81-3.78 (m, 1H),3.69-3.64 (m, 7H), 3.59-3.54 (m, 1H), 3.50-3.44 (m, 2H), 3.43-3.39 (m,4H), 3.37-3.35 (m, 2H). MS for C₁₈H₂₄Cl₂N₆O₃: 443.0 (MH⁺).

Example 86 Preparation of Compound 139 Synthesis of1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(Compound 139) Synthesis of (2S)-tert-butyl4-(3-(tert-butoxy)-2-hydroxypropyl)-2-(hydroxymethyl)piperazine-1-carboxylate

A mixture of (S)-tert-butyl 2-(hydroxymethyl)piperazine-1-carboxylate(850.9 mg, 3.93 mmol) and 2-(tert-butoxymethyl)oxirane (850 mg, 6.46mmol) in ethanol (10 mL) was heated at 120° C. for 30 min usingmicrowave. The mixture was concentrated to dryness. The residue waspurified with flash column chromatography on silica gel using 1-10%methanol in dichloromethane to afford a oil as the product inquantitative yield. 1H NMR (500 MHz, Chloroform-d) δ 4.09 (s, 1H), 3.84(m, 3H), 3.38 (dt, J=9.0, 3.7 Hz, 1H), 3.28 (m, 3H), 3.04 (dd, J=24.2,11.7 Hz, 1H), 2.88-2.80 (m, 2H), 2.48-2.32 (m, 3H), 2.26-2.21 (m, 1H),2.13-2.08 (m, 1H), 1.44 (s, 9H), 1.17 (d, 9H). MS for C₁₇H₃₄N₂O₅: 347.2(MH⁺).

Synthesis of1-(tert-butoxy)-3-((S)-3-(hydroxymethyl)piperazin-1-yl)propan-2-ol diHCl

(S)-Tert-butyl4-((S)-2-hydroxy-3-methoxypropyl)-2-(hydroxymethyl)piperazine-1-carboxylate(1.057 g, 3.05 mmol) was dissolved in ethanol (5 mL), 4 N HCl in dioxane(6 mL) was added: The mixture was stirred at room temperature for 3 h.The mixture was concentrated to remove all of solvents. The residue wasdried under high vacuum to afford the product (911.9 mg) in 94% yield.MS for C₁₂H₂₆N₂O₃: 247.2 (MH⁺).

Synthesis of1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol

A mixture of 5-amino-3,6-dichloro-1,2,4-triazine (251.5 mg, 1.524 mmol),diisopropylethylamine (2.0 mL, 11.48 mmol),(1-(tert-butoxy)-3-((S)-3-(hydroxymethyl) piperazin-1-yl)propan-2-ol diHCl (˜530 mg, 1.660 mmol) in dioxane (7 mL) was heated at 150 degree for4 h. The mixture was concentrated to remove all of solvent. The residuewas dissolved in dichloromethane, washed with aqueous sodium bicarbonatesolution. The organic solution was separated. The aqueous solution wassaturated with sodium chloride, extracted with dichloromethane (2×35mL). The combined organic solution was dried over anhydrous sodiumsulfate, concentrated to afford a residue. The residue was purified withflash column chromatography on silica using 1-10% methanol indichloromethane to afford product (229.9 mg) in 40% yield. 1H NMR (500MHz, Chloroform-d) δ 5.26 (br, 2H), 4.72 (s, 1H), 4.46 (d, J=13.4 Hz,1H), 4.02-3.83 (m, 3H), 3.42-3.36 (m, 2H), 3.34-3.29 (m, 1H), 3.15 (ddt,J=24.8, 11.8, 2.0 Hz, 1H), 2.96 (ddt, J=22.3, 11.4, 2.0 Hz, 1H),2.52-2.36 (m, 3H), 2.31 (m, 1H), 2.29-2.15 (m, 1H), 1.18 (d, 9H). MS forC₁₅H₂₇ClN₆O₃: 375.2 (MH⁺).

Synthesis of1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(Compound 139)

(2,3-Dichlorophenyl)boronic acid (217.9 mg, 1.142 mmol),1-((S)-4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(228 mg, 0.608 mmol) and cesium carbonate (626.7 mg, 1.904 mmol) wasdissolved in water/dioxane (3.5/10 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (135.7 mg, 0.117 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 3.5 h using microwave. The mixture wasconcentrated to remove organic solvents. The residue was mixed withbrine, extracted with dichloromethane (3×50 mL). The combined organicsolution was dried over anhydrous sodium sulfate, concentrated. Theresidue was purified twice with flash column chromatography on silicagel using 1-10% methanol in dichloromethane to afford the product (223.1mg) in 76% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.56 (dd, J=7.4, 2.1Hz, 1H), 7.40-7.28 (m, 2H), 4.90 (br, 1H), 4.75 (s, 2H), 4.63 (br, 1H),4.05-3.95 (m, 2H), 3.90 (m, 1H), 3.51-3.40 (m, 2H), 3.35-3.31 (m, 1H),3.18 (dd, J=27.4, 11.7 Hz, 1H), 3.00 (dd, J=23.9, 11.5 Hz, 1H),2.56-2.32 (m, 4H), 2.23 (td, J=11.9, 3.7 Hz, 1H), 1.19 (d, 9H). MS forC₂₁H₃₀Cl₂N₆O₃: 485.2 (MH⁺).

Example 87 Preparation of Compound 140 Synthesis of3-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)propane-1,2-dioldi HCl salt (Compound 140)

(1-((S)-4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol (85.5 mg, 0.176 mmol) wasstirred in 4 N HCl in dioxane (2 mL) for 65 h. The mixture wasconcentrated to remove all of solvents. The residue was dried under highvacuum to afford the product as HCl salt in quantitative yield. ¹H NMR(500 MHz, Methanol-d₄) δ 7.83-7.79 (m, 1H), 7.56-7.49 (m, 2H), 4.19-3.73(m, 6H), 3.68-3.57 (m, 11H), 3.52-3.32 (m, 4H). MS for C₁₇H₂₂C₁₂N₆O₃:429.0 (MH⁺).

Example 88 Preparation of Compound 141 Synthesis of6-(2,3-dichlorophenyl)-3-(4,7-diazaspiro[2.5]octan-4-yl)-1,2,4-triazin-5-amine(Compound 41) Synthesis of tert-butyl4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (108.5 mg,0.658 mmol), diisopropylethylamine (0.5 mL, 2.87 mmol), tert-butyl2-(4,7-diazaspiro[2.5]octan-7-yl)acetate (154.8 mg, 0.650 mmol) indioxane (2.5 mL). The mixture was heated at 155° C. for 9.5 h usingmicrowave. The mixture was concentrated to remove all of solvent. Theresidue was dissolved in dichloromethane, washed with aqueous sodiumbicarbonate solution. The organic solution was separated. The aqueoussolution was mixed with brine, extracted with dichloromethane (2×35 mL).The combined organic solution was dried over anhydrous sulfate,concentrated to afford a residue. The residue was purified with flashcolumn chromatography on silica using 1-10% methanol in dichloromethaneto afford product (118.3 mg) in 53% yield. ¹H NMR (500 MHz,Chloroform-d) δ 5.24 (s, 2H), 3.91 (t, J=4.5 Hz, 2H), 3.42 (m, 2H), 3.33(s, 2H), 1.43 (s, 9H), 0.96 (m, 4H). MS for C₁₄H₂₁ClN₆O₂: 341.2 (MH⁺).

Synthesis of tert-butyl4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate

(2,3-Dichlorophenyl)boronic acid (678 mg, 3.55 mmol), tert-butyl4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate(600 mg, 1.76 mmol) and cesium carbonate (1.8595 g, 6.56 mmol) wasdissolved in water/dioxane (6/20 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (294 mg, 0.255 mmol) wasadded. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 4.5 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×80 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified twicewith flash column chromatography on silica gel using 1-10methanol/dichloromethane, 30-100% ethyl acetate/hexane to afford product(611.5 mg) in 77% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.56 (dd,J=7.9, 1.7 Hz, 1H), 7.41-7.30 (m, 2H), 4.76 (s, 2H), 4.01 (s, 2H), 3.50(s, 2H), 3.40 (s, 2H), 1.45 (s, 9H), 1H), 1.07 (s, 2H), 0.97 (s, 2H). MSfor C₂₀H₂₄Cl₂N₆O₂: 451.0 (MH⁺).

Synthesis of6-(2,3-dichlorophenyl)-3-(4,7-diazaspiro[2.5]octan-4-yl)-1,2,4-triazin-5-amine(Compound 141)

Tert-butyl4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4,7-diazaspiro[2.5]octane-7-carboxylate(611.5 mg, 1.355 mmol) was dissolved in methanol (1.0 mL), 4N HCl indioxane (3.0 mL) was added. The mixture was stirred at room temperaturefor 4 h 40 min. The mixture was concentrated to remove the solvents. Theresidue was dried under high vacuum to afford white powder. 59.4 mg ofproduct was kept as HCl salt. The other was dissolved in water,saturated potassium bicarbonate solution was added, and then extractedwith dichloromethane (3×25 mL). The combined organic solution was washedwith brine, dried over anhydrous sodium sulfate, concentrated to affordthe product as free base (410.4 mg). ¹H NMR (500 MHz, Chloroform-d) δ7.56 (dd, J=7.9, 1.7 Hz, 1H), 7.40-7.38 (m, 1H), 7.33 (t, J=7.5 Hz, 1H),4.73 (s, 2H), 4.04 (s, 2H), 2.94 (t, J=5.0 Hz, 2H), 2.84 (s, 2H), 1.10(s, 2H), 0.91 (s, 2H). MS for C₁₅H₁₆Cl₂N₆: 351.0 (MH⁺).

Example 89 Preparation of Compound 142 Synthesis of6-(2,3-dichlorophenyl)-3-(2,2-dimethylpiperazin-1-yl)-1,2,4-triazin-5-aminedi HCl salt (Compound 142) Synthesis of tert-butyl4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate

A vial was charged with 5-amino-3,6-dichloro-1,2,4-triazine (736 mg,4.46 mmol), diisopropylethylamine (2.0 mL, 11.48 mmol), tert-butyl2-(3,3-dimethylpiperazin-1-yl)acetate (1.0875 g, 4.52 mmol) in dioxane(8 mL). The mixture was heated at 155° C. for 12 h using microwave. Themixture was concentrated to remove all of solvent. The residue wastreated with saturated sodium bicarbonate solution, extracted withdichloromethane (4×50 mL). The combined organic solution was washed withbrine, dried over anhydrous sodium sulfate, concentrated. The residuewas separated with flash column chromatography on silica gel using 1-10%methanol in dichloromethane, and 30-100% ethyl acetate/Hexane to affordproduct (201.8 mg) in 13% yield. ¹H NMR (500 MHz, Chloroform-d) δ 5.12(s, 2H), 4.06-4.02 (m, 2H), 3.52-3.46 (m, 2H), 1.50 (s, 6H), 1.44 (s,9H). MS for C₁₄H₂₃ClN₆O₂: 343.2 (MH⁺).

Synthesis of tert-butyl4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate

(2,3-dichlorophenyl)boronic acid (174.1 mg, 0.912 mmol), tert-butyl4-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate(179 mg, 0.522 mmol) and cesium carbonate (0.520 g, 1.58 mmol) wasdissolved in water/dioxane (2/7 mL). The mixture was degassed withnitrogen, tetrakis(triphenylphosphine)palladium (136.5 mg, 0.118 mmol)was added. The mixture was purged with nitrogen for a few minutes, andstirred at 90° C. for 2 h. The mixture was concentrated to removeorganic solvents. The residue was mixed with brine, extracted withdichloromethane (3×80 mL). The combined organic solution was dried overanhydrous sodium sulfate, concentrated. The residue was purified withflash column chromatography on silica gel using 1-10%methanol/dichloromethane, 30-70% ethyl acetate/hexane to afford product(158.3 mg) in 67% yield. ¹H NMR (500 MHz, Chloroform-d) δ 7.55-7.53 (m,1H), 7.37-7.30 (m, 2H), 4.66 (s, 2H), 4.18-4.15 (m, 2H), 3.56-3.51 (m,4H), 1.58 (d, J=2.5 Hz, 6H), 1.46 (s, 9H). MS for C₂₀H₂₆Cl₂N₆O₂: 453.2(MH⁺).

Synthesis of6-(2,3-dichlorophenyl)-3-(2,2-dimethylpiperazin-1-yl)-1,2,4-triazin-5-aminedi HCl salt (Compound 142)

Tert-butyl4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3,3-dimethylpiperazine-1-carboxylate(158 mg, 0.349 mmol) was dissolved in methanol (1 mL), 4 N HCl indioxane (0.6 mL) was added. The mixture was stirred at room temperaturefor 5 h. The mixture was concentrated to remove the solvents. Theresidue was dried under high vacuum to afford white powder as HCl salt(132.4 mg). The yield was 89%. ¹H NMR (500 MHz, Methanol-d₄) δ 7.79 (dd,J=7.8, 1.9 Hz, 1H), 7.55-7.42 (m, 2H), 4.01-3.95 (m, 2H), 3.60 (t, J=5.6Hz, 2H), 3.46 (s, 2H), 3.35 (s, 2H), 1.80 (s, 6H). MS for C₁₅H₁₈Cl₂N₆:353.0 (MH⁺).

Example 90 Preparation of Compound 143

(S)-1-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol(Compound 143)

Compound 143,(S)-1-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol,is prepared as follows.

Step-1: Preparation of(S)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol

3,6-Dichloro-1,2,4-triazin-5-amine (1.00 eq.),(S)-1-(2-amino-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol(1.5 eq.) and NaHCO₃ (2 eq.) are added to a 1,4-dioxane solution anddegassed, for 5-10 min. The reaction mixture was stirred at 85° C. for12 h. After completion of the reaction, the crude product is purified bycolumn chromatography to afford(S)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol.

Step-2: Preparation of(S)-1-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol(Compound 143)

To a suspension of(S)-1-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol(Compound 5) (1.0 eq.), (2,3-dichlorophenyl)boronic acid (1.7 eq.),cesium carbonate (3.3 eq.) in 1,4-dioxane:water (2:1) is addedPd(PPh₃)₄(0.05 eq.) and heated to 90° C. for 8 h. Crude afterevaporation of the solvent upon purification by flash chromatographyaffords(S)-1-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropoxy)-3-(2,2,2-trifluoroethoxy)propan-2-ol(Compound 143). The free base is dissolved in 2 mL of 4N hydrochloridein 2-propanol. The mixture is concentrated under vacuum to affordproduct as hydrochloride salt.

Example 91 Preparation of Compound 144

1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol(Compound 144)

1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol(compound 6) is prepared according to the following steps:

Step 1: Preparation of1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol

To a solution of1-amino-3-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)propan-2-ol (1.0 equiv.)in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine (1.0 eq.).Reaction mixture is then charged with sodium bicarbonate (3.0 eq.) andstirred at 90° C. for 12 h. Evaporation of the solvent and purificationof the residue by flash chromatography yields(1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol.

Step-2: Preparation of1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol(compound 144)

To a suspension of(1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol(compound 7) (1.0 eq.), (2,3-dichlorophenyl)boronic acid (1.7 eq.),cesium carbonate (3.3 equiv.) in 1,4-dioxane:water (2:1) is addedPd(PPh₃)₄(0.05 eq.) and heated to 90° C. for 6 h. Crude afterevaporation of the solvent is purified by flash chromatography to afford1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(trifluoromethoxy)-ethoxy)ethoxy)propan-2-ol(compound 144). The free base is dissolved in 2 mL of 4N hydrochloridein 2-propanol. The mixture is concentrated under vacuum to affordproduct as hydrochloride salt.

Example 92 Preparation of Compound 145

1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol(Compound 145)

1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol(compound 145) is prepared according to the following steps:

Step 1: Preparation of1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol

To a solution of1-amino-3-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)propan-2-ol (1.0eq.) in 1,4-dioxane (10 mL) is added 5-amino-3,6-dichloro-triazine (1.0eq.). Reaction mixture is then charged with sodium bicarbonate (3.0 eq.)and stirred at 90° C. for 10 h. Evaporation of the solvent andpurification of the residue by flash chromatography yields1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol.

Step-2: Preparation of1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol(compound 145)

To a suspension of(1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)ethoxy)ethoxy)propan-2-ol(1.0 eq.), (2,3-dichlorophenyl) boronic acid (1.7 eq.), cesium carbonate(3.3 eq.) in 1,4-dioxane:water (2:1) is added Pd(PPh₃)₄(0.05 eq.) andheated to 90° C. Crude after evaporation of the solvent is purified byflash chromatography and yields1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-(2,2,2-trifluoroethoxy)-ethoxy)ethoxy)propan-2-ol.The free base is dissolved in 2 mL of 4N hydrochloride in 2-propanol.The mixture is concentrated under vacuum to afford product ashydrochloride salt.

Example 93 Preparation of Compound 146 The Synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol(Compound 146)

Step 1. The synthesis of (S)-tert-butyl(2-((3,3,3-trifluoro-2-hydroxypropyl)amino)ethyl)carbamate is as Follows

N-Boc-ethylenediamine (4 g, 25 mmol) and (S)-2-(trifluoromethyl)oxirane(3.36 g, 30 mmol) are dissolved in methanol (50 mL). The solution isstirred at 90° C. for 1.5 hours. The solvent is evaporated at reducedpressure. The obtained crude (6.8 g) is used for next step withoutfurther purification.

Step 2. The synthesis of(S)-3-((2-aminoethyl)amino)-1,1,1-trifluoropropan-2-ol

The (S)-tert-butyl(2-((3,3,3-trifluoro-2-hydroxypropyl)amino)ethyl)carbamate crude (6.8 g)is dissolved in methanol (20 mL), in which HCl in methanol (2N, 60 mL)is added at room temperature. The solution is stirred at roomtemperature for 2 hours. The solvent is evaporated at reduced pressure.The obtained crude is washed with saturated NaHCO₃ solution (50 mL) andextracted with DCM (50 mL×3). The organic phase is combined, dried offby anhydrous Na2SO4, and evaporated to afford(S)-3-((2-aminoethyl)amino)-1,1,1-trifluoropropan-2-ol crude (4.4 g),which is used for next step without further purification.

Step 3. The synthesis of(S)-3-((2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol

(S)-3-((2-aminoethyl)amino)-1,1,1-trifluoropropan-2-ol (4.3 g, 25 mmol)and 3,6-dichloro-1,2,4-triazin-5-amine (4.53 g, 27.5 mmol) are dissolvedin anhydrous dioxane (14 mL). TEA (4.4 mL, 31.6 mmol) is added intosolution. The reaction solution is heated at 95° C. for 1 hour. Themixture is cooled to room temperature and white precipitate is observed.The mixture is filtered to collect the solution. The solution isconcentrated to remove the solvents. The residue is used for next stepwithout further purification.

Step 4.(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol

(2,3-dichlorophenyl)boronic acid (5.25 g, 27.5 mmol),(S)-3-((2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol(7.52 g, 25 mmol), and cesium carbonate (16.29 g, 50 mmol) are added inmixture of water and dioxane (50 mL and 150 mL, respectively). After themixture is degassed and filled with nitrogen,tetrakis(triphenylphosphine)palladium (5.78 g, 5 mmol) is added. Themixture is purged with nitrogen again for a few minutes, and stirred at85° C. for 4 hours. The mixture is cooled to room temperature. Yellowprecipitation is formed. The mixture is filtered and the solid is washedwith dioxane. The solution is collected and concentrated to removeorganic solvents.

The residue is mixed with brine (150 mL) and extracted with DCM (3×50mL). The combined organic solution is dried over anhydrous Na₂SO₄ andconcentrated. The residue is purified with flash column chromatographyusing MeOH/DCM (0-10%) to afford product(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol(4.9 g, 11.92 mmol, over all yield 47.7%).

Example 94 Preparation of Compound 147 The Synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol

The synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-olis performed following the above procedure by usingN-Boc-N-methylethylenediamine as starting material:

Example 95 Preparation of Compound 148 The Synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-ol

The synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-olis performed following the above procedure by using tert-Butyl2-(methylamino)ethylcarbamate as starting material.

Example 96 Preparation of Compound 149 The Synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-ol

The synthesis of(S)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-olis performed following the above procedure by using tert-butylmethyl(2-(methylamino)ethyl)carbamate as starting material.

Example 97 Preparation of Compound 150 The Synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol

The synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-olis performed following the above procedure by using(R)-2-(trifluoromethyl)oxirane and N-Boc-ethylenediamine as startingmaterial:

Example 98 Preparation of Compound 151 The Synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol(Compound 151)

The synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)amino)-1,1,1-trifluoropropan-2-ol:is performed following the above procedure by usingN-Boc-N-methylethylenediamine as starting material.

Example 99 Preparation of Compound 152 The Synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-ol

The synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-olis performed following the above procedure by using tert-Butyl2-(methylamino)ethylcarbamate as starting material.

Example 100 Preparation of Compound 154 The Synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-ol

The synthesis of(R)-3-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-1,1,1-trifluoropropan-2-olis carried out following the above procedure by using tert-butylmethyl(2-(methylamino)ethyl)carbamateethylcarbamate as startingmaterial.

Example 101 Preparation of Compound 155 The Synthesis of(S)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol

The synthesis of(S)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-olis carried out as set forth below using (S)-epichlorohydrin andtert-butyl (2-(methylamino)ethyl)carbamate as starting materials.

Example 102 Preparation of Compound 156 The Synthesis of(S)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol

The synthesis of(S)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-olis performed following the synthetic methodology shown below using(S)-epichlorohydrin and tert-butyl methyl(2-(methylamino)ethyl)carbamateas starting materials.

Example 103 Preparation of Compound 157 The Synthesis of(R)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol

The synthesis of(R)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-olis conducted following the synthetic methodology shown below using(R)-epichlorohydrin and tert-butyl (2-(methylamino)ethyl)carbamate asstarting materials.

Example 104 Preparation of Compound 158 The Synthesis of(R)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-ol(Compound 158)

The synthesis of(R)-1-((2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)(methyl)amino)-3-(2,2,2-trifluoroethoxy)propan-2-olis performed following the synthetic methodology shown below using(R)-epichlorohydrin and tert-butyl methyl(2-(methylamino)ethyl)carbamateas starting materials.

Example 105 Preparation of Compound 159 Preparation of(S)-1-(((R)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)amino)-3-methoxypropan-2-ol,hydrochloride salt (Compound 159)

(S)-1-(((R)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)amino)-3-methoxypropan-2-olwas prepared according to the following steps.

Step 1: Preparation of (R)-tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)carbamate: A0.5-2 mL microwave vial was charged with (R)-tert-butylpyrrolidin-3-ylcarbamate, hydrochloride (0.145 g, 0.65 mmol),3,6-dichloro-1,2,4-triazin-5-amine (0.082 g, 0.50 mmol), dry 1,4-dioxane(1 mL) and triethylamine (0.21 mL, 1.50 mmol), and the mixture heated ina microwave vial at 120° C. for 45 min. The mixture was carried forwardto the next step without further purification. MS (EI) for C₁₃H₂₁ClN₆O₂:329.2 (MH⁺).

Step 2: Preparation of(R)-3-(3-aminopyrrolidin-1-yl)-6-chloro-1,2,4-triazin-5-amine: The crudereaction mixture from the last step was diluted with methanol (2 mL) and4 M HCl in dioxane (2.5 mL), and the resultant solution aged at RT for 5min, before warming to 60° C. The mixture was removed from the heatafter 20 min, concentrated to dryness, and the residue partitionedbetween CHCl3/IPA (3:1, 3×5 mL) and 2 M sodium carbonate (5 mL). Thecombined organic layers were dried (sodium sulfate), filtered andconcentrated to a yellow oil (crude 109 mg), which was carried forwardto the next step without further purification. MS (EI) for C₇H₁1ClN₆:215.0 (MH⁺).

Step 3: Preparation of(S)-1-(((R)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)amino)-3-methoxypropan-2-ol:A suspension of(R)-3-(3-aminopyrrolidin-1-yl)-6-chloro-1,2,4-triazin-5-amine (107 mg,0.50 mmol) and (S)-2-(methoxymethyl)oxirane (0.045 mL, 0.50 mmol) in dryEthanol (3 mL) was heated to 60° C., whereupon it dissolved. Neat(S)-2-(methoxymethyl)oxirane (0.045 mL, 0.50 mmol) was added and themixture heated at 60° C. for 18 h. Additional(S)-2-(methoxymethyl)oxirane (0.023 mL, 0.25 mmol) was added after 16.5h. The mixture was evaporated from toluene (10 mL) to afford a brown oil(crude 171 mg), which was used in the next step without furtherpurification. MS (EI) for C₁₁H₁₉ClN₆O₂: 303.1 (MH⁺).

Step 4: Preparation of(S)-1-(((R)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)amino)-3-methoxypropan-2-ol:A 20 mL septumed screw-capped vial was charged withtetrakis(triphenylphosphine)palladium (116 mg, 0.10 mmol), capped with aseptum, and purged with nitrogen, whereupon solutions of(S)-1-(((R)-1-(5-amino-6-chloro-1,2,4-triazin-3-yl)pyrrolidin-3-yl)amino)-3-methoxypropan-2-ol(171 mg, assumed 0.50 mmol) in nitrogen sparged dioxane (7 mL) and(2,3-dichlorophenyl)boronic acid (191 mg, 1.00 mmol) and cesiumcarbonate (505 mg, 1.55 mmol) in nitrogen-sparged water (2.3 mL) wereadded, and the stirred yellow suspension heated in a heat block at 90°C. for 1.3 h. The cooled mixture was partitioned between toluene (7 mL)and 2 M sodium hydroxide (3 mL), and the aqueous layer extracted withfurther toluene (7 mL). The combined organic layers were extracted with2 M H2SO4 (3 mL, 2×2 mL). The combined acid extracts were basified topH >12 with 4 M sodium hydroxide, and extracted with 1,2-DCE (2×mL). Thecombined DCE layers were dried (sodium sulfate), filtered andconcentrated. Reverse phase prep HPLC (2 injections; eluting with 15-35%acetonitrile in 10 mM aqueous ammonium formate on a 150×21.2 mm i.d., 10um Gemini C18 column) afforded, after freebasing with 1 M sodiumhydroxide/dichloromethane,(S)-1-(((R)-1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)pyrrolidin-3-yl)amino)-3-methoxypropan-2-olas a pale cream solid (49 mg, 23% over 4 steps). ¹H NMR (500 MHz,DMSO-d6) δ 7.71 (dd, J=8.1, 1.5 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.35(dd, J=7.7, 1.6 Hz, 1H), 6.74 (s, 2H), 4.75 (d, J=4.9 Hz, 1H), 3.70-3.62(m, 2H), 3.62-3.44 (m, 2H), 3.34-3.23 (m, 2H), 3.28 (dd, J=9.5, 5.6 Hz,2H), 3.25 (s, 3H), 2.60 (dd, J=11.7, 4.3 Hz, 1H), 2.07 (dq, J=12.7, 6.4,5.5 Hz, 1H), 1.82 (br s, 1H), 1.78 (dq, J=12.7, 6.4, 5.3 Hz, 1H); MS(EI) for C₁₇H₂₂C₁₂N₆O₂: 413.0 (MH⁺).

The free base (47 mg) was dissolved in acetonitrile (2 mL), treated with4 M HCl in dioxane (300 uL), concentrated to dryness. The residue wasdissolved in acetonitrile/water (10:1), and concentrated undercentrifugal evaporation to afford the dihydrochloride salt as a verypale orange glass.

Example 106 Preparation of Compound 160 Preparation of(S)-1-(((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-ol,hydrochloride salt (Compound 160)

(S)-1-(((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-olwas prepared according to the following steps.

Step 1: Preparation of tert-butyl((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)carbamate:As described for Example 105 above, tert-butyl(azetidin-3-ylmethyl)(methyl)carbamate (0.110 g, 0.55 mmol) and3,6-dichloro-1,2,4-triazin-5-amine (0.082 g, 0.50 mmol) were coupled toafford crude tert-butyl((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)carbamate(assumed 0.50 mmol), which was carried forward to the next step withoutfurther purification.

Step 2: Preparation of6-chloro-3-(3-((methylamino)methyl)azetidin-1-yl)-1,2,4-triazin-5-amine:As described for Example 105 above, tert-butyl((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)carbamate(assumed 0.50 mmol) was treated with 4 M HCl in dioxane (2.5 mL, 10mmol) to afford crude6-chloro-3-(3-((methylamino)methyl)azetidin-1-yl)-1,2,4-triazin-5-amine(137 mg, assumed 0.50 mmol), which was carried forward to the next stepwithout further purification.

Step 3: Preparation of(S)-1-(((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-ol:As described for Example 105 above,6-chloro-3-(3-((methylamino)methyl)azetidin-1-yl)-1,2,4-triazin-5-amine(137 mg, assumed 0.50 mmol) and (S)-2-(methoxymethyl)oxirane (0.058 mL,0.65 mmol) were coupled to afford crude(S)-1-(((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-ol(assumed 0.50 mmol), which was carried forward to the next step withoutfurther purification.

Step 4: Preparation of(S)-1-(((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-ol:As described for Example 105 above, crude(S)-1-(((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-ol(assumed 0.50 mmol) and (2,3-di-chlorophenyl)boronic acid (191 mg, 1.00mmol) were coupled to afford, after reverse phase prep HPLC purifycation(2 injections; eluting with 30-45% acetonitrile in 10 mM aqueousammonium hydroxide on a 150×21.2 mm i.d., 10 um Gemini C18 column),(S)-1-(((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)methyl)(methyl)amino)-3-methoxypropan-2-olas a colorless solid (45 mg, 21% over 4 steps). ¹H NMR (500 MHz, CDCl₃)δ 7.56 (dd, J=7.4, 2.3 Hz, 1H), 7.38-7.30 (m, 2H), 5.01 (s, 2H),4.33-4.25 (m, 2H), 3.86 (ddd, J=7.0, 5.0, 2.3 Hz, 3H), 3.44 (dd, J=9.9,3.9 Hz, 1H), 3.39 (s, 3H), 3.37 (dd, J=9.9, 5.6 Hz, 1H), 3.33 (s, 1H),2.95 (ddt, J=9.9, 7.6, 3.9 Hz, 1H), 2.81 (dd, J=12.5, 7.8 Hz, 1H), 2.71(dd, J=12.5, 7.3 Hz, 1H), 2.49 (dd, J=12.5, 9.7 Hz, 1H), 2.39 (dd,J=12.5, 3.8 Hz, 1H), 2.30 (s, 3H); MS (EI) for C₁₈H₂₄Cl₂N₆O₂: 427.2(MH⁺).

The free base (45 mg) was dissolved in acetonitrile (2 mL), treated with4 M HCl in dioxane (265 uL), concentrated to dryness. The residue wasdissolved in acetonitrile/water (10:1), and concentrated undercentrifugal evaporation to afford the dihydrochloride salt as a verypale yellow solid foam.

Example 107 Preparation of Compound 161 Preparation of(2S)-1-(6-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-ol,hydrochloride salt (Compound 161)

(2S)-1-(6-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-olwas prepared according to the following steps.

Step 1: Preparation of tert-butyl6-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate:As described for Example 105 above, tert-butyl2,6-diazaspiro[3.5]nonane-2-carboxylate, hemioxalate (0.166 g, 0.53mmol) and 3,6-dichloro-1,2,4-triazin-5-amine (0.082 g, 0.50 mmol) werecoupled to afford crude tert-butyl6-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate(assumed 0.50 mmol), which was carried forward to the next step withoutfurther purification.

Step 2: Preparation of6-chloro-3-(2,6-diazaspiro[3.5]nonan-6-yl)-1,2,4-triazin-5-amine: Asdescribed for Example 105 above, tert-butyl6-(5-amino-6-chloro-1,2,4-triazin-3-yl)-2,6-diazaspiro[3.5]nonane-2-carboxylate(assumed 0.50 mmol) was treated with 4 M HCl in dioxane (2.5 mL, 10mmol) to afford crude6-chloro-3-(2,6-diazaspiro[3.5]nonan-6-yl)-1,2,4-triazin-5-amine (129mg, assumed 0.50 mmol), which was carried forward to the next stepwithout further purification.

Step 3: Preparation of(2S)-1-(6-(5-amino-6-chloro-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-ol:As described for Example 105 above,6-chloro-3-(2,6-diazaspiro[3.5]nonan-6-yl)-1,2,4-triazin-5-amine (129mg, assumed 0.50 mmol), and (S)-2-(methoxymethyl)oxirane (0.058 mL, 0.65mmol) were coupled to afford crude(2S)-1-(6-(5-amino-6-chloro-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-ol(assumed 0.50 mmol), which was carried forward to the next step withoutfurther purification.

Step 4: Preparation of(2S)-1-(6-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-ol:As described for Example 105 above, crude(2S)-1-(6-(5-amino-6-chloro-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-ol(assumed 0.50 mmol) and (2,3-dichlorophenyl)boronic acid (191 mg, 1.00mmol) were coupled to afford, after reverse phase prep HPLC purification(2 injections; eluting with 25-40% acetonitrile in 10 mM aqueousammonium hydroxide on a 150×21.2 mm i.d., 10 um Gemini C18 column),(2S)-1-(6-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-1,6-diazaspiro[3.5]nonan-1-yl)-3-methoxypropan-2-olas a pale yellow solid (12 mg, 5% over 4 steps). ¹H NMR (500 MHz, CDCl₃)δ 7.57 (dd, J=7.9; 1.7 Hz, 1H), 7.39 (dd, J=7.7, 1.7 Hz, 1H), 7.35 (t,J=7.7 Hz, 1H), 5.03 (s, 2H), 3.96 (s, 2H), 3.82 (s, 2H), 3.72 (dq,J=9.1, 4.4 Hz, 1H), 3.38 (s, 3H), 3.43-3.30 (m, 2H), 3.24 (dd, J=22.9,7.3 Hz, 2H), 3.01 (d, J=7.3 Hz, 1H), 2.92 (d, J=7.2 Hz, 1H), 2.59 (dd,J=12.0, 8.8 Hz, 1H), 2.51 (dd, J=12.0, 3.6 Hz, 1H), 1.82 (t, J=5.9 Hz,2H), 1.62 (t, J=6.0 Hz, 2H); MS (EI) for C₂₀H₂₆Cl₂N₆O₂: 453.2 (MH⁺).

The free base (11 mg) was dissolved in acetonitrile (2 mL), treated with4 M HCl in dioxane (50 uL), concentrated to dryness. The residue wasdissolved in acetonitrile/water (10:1), and concentrated undercentrifugal evaporation to afford the dihydrochloride salt as a verypale yellow solid foam.

Example 108 Preparation of Compound 162 Preparation of(2S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-ol,hydrochloride salt (Compound 162)

of(2S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-olwas prepared according to the following steps.

Step 1: Preparation of tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)carbamate:As described for Example 105 above, tert-butyl(3-methylpyrrolidin-3-yl)carbamate (0.260 g, 1.30 mmol),3,6-dichloro-1,2,4-triazin-5-amine (0.165 g, 1.00 mmol), dry 1,4-Dioxane(1 mL) and triethylamine (0.42 mL, 3.00 mmol), were coupled to affordcrude tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)carbamate(assumed 1.00 mmol), which was carried forward to the next step withoutfurther purification.

Step 2: Preparation of3-(3-amino-3-methylpyrrolidin-1-yl)-6-chloro-1,2,4-triazin-5-amine: Asdescribed for Example 105 above, tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)carbamate(assumed 1.00 mmol), was treated with 4 M HCl in dioxane (5 mL, 20 mmol)to afford crude3-(3-amino-3-methylpyrrolidin-1-yl)-6-chloro-1,2,4-triazin-5-amine (243mg, assumed 1.00 mmol), which was carried forward to the next stepwithout further purification.

Step 3: Preparation of(2S)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-ol:As described for Example 105 above,3-(3-amino-3-methylpyrrolidin-1-yl)-6-chloro-1,2,4-triazin-5-amine (243mg, assumed 1.00 mmol) and (S)-2-(methoxymethyl)oxirane (0.099 mL, 1.1mmol) were coupled to afford crude(2S)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-ol(assumed 1.00 mmol), which was carried forward to the next step withoutfurther purification. MS (EI) for C₁₂H₂₁ClN₆O₂: 317.2 (MH⁺).

Step 4: Preparation of(2S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-ol:As described for Example 105 above, crude((2S)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-ol(assumed 1.00 mmol), and (2,3-dichlorophenyl)boronic acid (382 mg, 2.00mmol) were coupled to afford, after reverse phase prep HPLC purification(3 injections; eluting with 15-35% acetonitrile in 10 mM aqueousammonium formate on a 150×21.2 mm i.d., 10 um Gemini C18 column), andfreebasing with 1 M sodium hydroxide/dichloromethane,(2S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-methylpyrrolidin-3-yl)amino)-3-methoxypropan-2-ol(83 mg, 19% over 4 steps). ¹H NMR (500 MHz, DMSO-d6) δ 7.70 (dd, J=8.0,1.5 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.34 (dd, J=7.6, 1.5 Hz, 1H), 6.86(s, 2H), 4.70 (dd, J=4.9, 1.9 Hz, 1H), 3.62-3.54 (m, 4H), 3.31 (dt,J=9.9, 5.0 Hz, 2H), 3.25 (ddd, J=9.4, 5.9, 3.5 Hz, 1H), 3.23 (2singlets, 3H, diastereomers), 2.67-2.40 (m, 2H), 1.92 (d, J=7.4 Hz, 1H),1.86-1.60 (m, 2H), 1.21 (s, 3H); MS (EI) for C₁₈H₂₄Cl₂N₆O₂: 427.2 (MH⁺).

The free base (80 mg) was dissolved in acetonitrile (2 mL), treated with4 M HCl in dioxane (470 uL), concentrated to dryness. The residue wasdissolved in acetonitrile/water (10:1), and concentrated undercentrifugal evaporation to afford the dihydrochloride salt as a lightyellow-orange solid.

Example 109 Preparation of Compound 163 Preparation of(S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-ol,hydrochloride salt (Compound 163)

(S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-olwas prepared according to the following steps.

Step 1: Preparation of tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)carbamate: Asdescribed for Example 105 above, tert-butyl azetidin-3-ylcarbamate, HCl(0.136 g, 0.65 mmol), and 3,6-dichloro-1,2,4-triazin-5-amine (0.082 g,0.50 mmol) were coupled to afford crude tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)carbamate (assumed0.50 mmol), which was carried forward to the next step without furtherpurification.

Step 2: Preparation of3-(3-aminoazetidin-1-yl)-6-chloro-1,2,4-triazin-5-amine: As describedfor Example 105 above, tert-butyl(1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)carbamate (assumed0.50 mmol), was treated with 4 M HCl in dioxane (2.5 mL, 10 mmol) toafford crude 3-(3-aminoazetidin-1-yl)-6-chloro-1,2,4-triazin-5-amine (57mg, assumed 0.28 mmol), which was carried forward to the next stepwithout further purification.

Step 3: Preparation of(S)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-ol:As described for Example 105 above, crude3-(3-aminoazetidin-1-yl)-6-chloro-1,2,4-triazin-5-amine (57 mg, assumed0.28 mmol) and (S)-2-(methoxymethyl)oxirane (0.033 mL, 0.36 mmol) werecoupled to afford(S)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-ol(90 mg, assumed 0.28 mmol), which was carried forward to the next stepwithout further purification. MS (EI) for C₁₀H₁₇ClN₆O₂: 289.0 (MH⁺).

Step 4: Preparation of(S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-ol:As described for Example 105 above, crude(S)-1-((1-(5-amino-6-chloro-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-ol(90 mg, assumed 0.28 mmol) and (2,3-dichlorophenyl)boronic acid (191 mg,1.00 mmol) were coupled to afford, after reverse phase prep HPLCpurification (2 injections; eluting with 15-35% acetonitrile in 10 mMaqueous ammonium formate on a 150×21.2 mm i.d., 10 um Gemini C18column), and freebasing with 1 M sodium hydroxide/dichloromethane,(S)-1-((1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)amino)-3-methoxypropan-2-olas a film (8.6 mg, 4% over 4 steps). ¹H NMR (500 MHz, CDCl₃) δ 7.58 (dd,J=7.3, 2.3 Hz, 1H), 7.38 (dd, J=7.7, 2.3 Hz, 1H), 7.35 (t, J=7.6 Hz,1H), 4.96 (s, 2H), 4.41 (t, J=8.2 Hz, 2H), 3.96 (dt, J=9.3, 4.8 Hz, 2H),3.89 (dq, J=10.2, 3.7 Hz, 1H), 3.82 (tt, J=7.0, 4.9 Hz, 1H), 3.47 (dd,J=9.7, 3.8 Hz, 1H), 3.42 (dd, J=9.7, 6.3 Hz, 1H), 3.41 (s, 3H), 2.77(dd, J=12.1, 3.8 Hz, 1H), 2.70 (dd, J=12.1, 7.8 Hz, 1H), 2.18 (br s,2H); MS (EI) for C₁₆H₂₀Cl₂N₆O₂: 399.0 (MH⁺).

The freebase (8.6 mg) was dissolved in acetonitrile (2 mL), treated with4 M HCl in dioxane (50 uL), concentrated to dryness. The residue wasdissolved in acetonitrile/water (10:1), and concentrated undercentrifugal evaporation to afford the dihydrochloride salt as a verypale yellow solid foam.

Example 110 Preparation of Compound 153

1-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol(Compound 153)

1-((A-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol(Compound 1) was prepared according to the following steps.

Step 1: Preparation of1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol

3,6-Dichloro-1,2,4-triazin-5-amine (500 mg, 3.03 mmol) and1-amino-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol (703 mg, 3.64 mmol)were dissolved in 10 mL of 1,4-dioxane. Reaction mixture was thencharged with sodium bicarbonate (382 mg, 4.55 mmol) and stirred at 90°C. for 10 h. Evaporation of the solvent and purification of the residueby column chromatography afforded1-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol(compound 2) (530 mg, 54.4% yield).

Step 2: Preparation of1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol(Compound 153)

1-((5-Amino-6-chloro-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)Propan-2-ol(530 mg, 1.647 mmol) and (2,3-dichlorophenyl)boronic acid (534 mg, 2.80mmol) were dissolved in 20 mL of 1,4-dioxane. Pd(PPh₃)₄(190 mg, 0.165mmol), K₂HPO₄ (631 mg, 3.62 mmol) and 5 ml of DI water were added to theabove reaction mixture and de gassed for 15 minutes. Then reactionmixture was stirred at 90° C. for 8 h. Crude after evaporation of thesolvent upon purification by column chromatography yielded1-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-3-(2-(2-methoxyethoxy)ethoxy)propan-2-ol(compound 1) as light yellow solid (310 mg, 43.5% yield). ¹H NMR (500MHz, CDCl₃): δ 7.70 (dd, 1H), 7.45 (t, 1H), 7.35 (d, 1H), 6.20-7.30 (bs,3H), 4.80-5.30 (bs, 1H), 3.75-3.85 (m, 1H), 3.46-3.59 (m, 6H), 3.30-3.46(m, 5H), 3.1.7-3.29 (bs, 4H); MS (ESI) for C₁₇H₂₃Cl₂N₅O₄: 432.3016(MH⁺). The free base was dissolved in 4M hydrochloride in 2-propanol.The mixture was concentrated under vacuum to afford product ashydrochloride salt.

Example 111 Preparation of Compound 166

6-(2,3-Dichlorophenyl)-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine(Compound 166)

6-(2,3-Dichlorophenyl)-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-aminewas prepared according to the following steps.

Step 1: Preparation of6-chloro-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine

3,6-dichloro-1,2,4-triazin-5-amine (400 mg, 2.425 mmol) andO-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)hydroxylamine (652 mg, 3.64 mmol)were dissolved in 10 mL of 1,4-dioxane. Reaction mixture is then chargedwith sodium bicarbonate (407 mg, 4.85 mmol) and stirred at 90° C. for 10h. Reaction mixture was filtered to remove salt and evaporation of thesolvent under vacuum gave crude product. Purification of the crudeproduct by column chromatography yielded6-chloro-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine(260 mg, 34.8% yield).

Step 2: Preparation of6-(2,3-dichlorophenyl)-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine(Compound 166)

6-Chloro-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine(260 mg, 0.845 mmol) and (2,3-dichlorophenyl)boronic acid (242 mg, 1.267mmol) were dissolved in 10 mL of 1,4-dioxane. Pd(PPh₃)₄(78 mg, 0.068mmol), K₂HPO₄ (294 mg, 1.690 mmol) and 3 ml of DI water were added tothe above reaction mixture and degassed for 15 minutes. Then thereaction mixture was stirred at 90° C. for 8 h. Crude after evaporationof the solvent upon purification by flash chromatography yielded6-(2,3-dichlorophenyl)-3-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)amino)-1,2,4-triazin-5-amine(compound 166) as off white solid (60 mg, 16.98% yield). ¹H NMR (500MHz, DMSO-d6): δ 7.70-7.80 (d, 1H), 7.40-7.50 (t, 1H), 7.30-7.40 (d,1H), 6.45-7.10 (bs 2H), 6.35-6.45 (s, 1H), 3.96-4.06 (t, 2H), 3.65-3.70(t, 2H), 3.55-3.60 (m, 2H), 3.49-3.55 (m, 4H), 3.42-3.47 (m, 2H),3.23-3.26 (s, 3H); MS (ESI) for C₁₆H₂₁Cl₂N₅O₄: 418.2750 (MH⁺). The freebase was dissolved in 4M hydrochloride in 2-propanol. The mixture wasconcentrated under vacuum to afford product as hydrochloride salt.

Example 112 Preparation of Compound 167

6-(2,3-Dichlorophenyl)-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 167)

6-(2,3-dichlorophenyl)-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 167) was prepared according to the following steps.

Step 1: Preparation of6-chloro-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine

3,6-Dichloro-1,2,4-triazin-5-amine (54.3 mg, 3.29 mmol) and2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethanamine (1000 mg, 4.60 mmol)were dissolved in 10 mL of 1,4-dioxane. Reaction mixture was thencharged with sodium bicarbonate (414 mg, 4.93 mmol) and stirred at 90°C. for 10 h. Reaction mixture was filtered to remove salt andevaporation of the solvent under vacuum gave crude product. Purificationof the crude product by column chromatography yielded6-chloro-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(960 mg, 86% yield).

Step 2: Preparation of6-(3,4-dichlorophenyl)-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(compound 167)

6-chloro-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(960 mg, 2.78 mmol) and (2,3-dichlorophenyl)boronic acid (901 mg, 4.72mmol) were dissolved in 16 mL of 1,4-dioxane. Pd(PPh₃)₄(321 mg, 0.278mmol), K₂HPO₄ (1064 mg, 6.11 mmol) and 4 ml of DI water were added tothe above reaction mixture and de gassed for 15 minutes. Then reactionmixture is stirred at 90° C. for 8 h. Crude after evaporation of thesolvent upon purification by flash chromatography yielded6-(3,4-dichlorophenyl)-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(compound 167) as off white solid (90 mg, 7.11% yield). ¹H NMR (500 MHz,DMSO): δ 7.65-7.72 (dd, 1H), 7.40-7.45 (t, 1H), 7.35-7.40 (d, 1H),4.15-4.20 (m, 2H), 3.65-3.70 (m, 2H), 3.50-3.60 (m, 6H), 3.28-3.40 (m,2H), 3.20-3.30 (m, 2H); MS (ESI) for C₁₆H₁₈Cl₂F₃N₅O₃: 456.07 (MH⁺). Thefree base was dissolved in 4M hydrochloride in 2-propanol. The mixturewas concentrated under vacuum to afford product as hydrochloride salt.

Example 113 Preparation of Compound 116 Preparation of6-(2,3-dichlorophenyl)-N3-(2-morpholinoethyl)-1,2,4-triazine-3,5-diamine(Compound 116)

Preparation of6-chloro-N3-(2-morpholinoethyl)-1,2,4-triazine-3,5-diamine:5-Amino-3,6-dichloro-1,2,4-triazine (165 mg, 1.00 mmol) was dissolved indioxane (10 mL) at room temperature. Et₃N (0.307 mL, 2.20 mmol) wasadded, followed by addition of 2-morpholinoethanamine (0.196 mL, 1.49mmol). The resulting mixture was stirred at 95° C. for 4 hours. Thereaction mixture was stirred at 95° C. for overnight. After cooling toambient temperature, insoluble was filtrated and washed with 10 mL ofethyl acetate. Filtrate was concentrated at 50° C. with reducedpressure. Residue was mixed with 100 mL of DCM and stirred for 10minutes. Insoluble was collected through filtration and washed with DCM(10 mL×2). The precipitate was dried in vacuum for overnight to give thedesired product 111 mg (36% yield). LC-MS (ESI, MH⁺) 259

Preparation of6-(2,3-dichlorophenyl)-N3-(2-morpholinoethyl)-1,2,4-triazine-3,5-diamine:(2,3-dichlorophenyl)boronic acid (387.2 mg, 2.03 mmol),6-chloro-N3-(2-morpholinoethyl)-1,2,4-triazine-3,5-diamine (350 mg, 1.35mmol), cesium carbonate (882 mg, 2.71 mmol) were dissolved in 35 mLdegassed dioxane/H2O (3:1) and tetrakis(triphenylphosphine)palladium(392 mg, 0.338 mmol) was added under nitrogen atmosphere. The reactionmixture was stirred at 85° C. for 1 hour to completion. After cooling toambient temperature, the solvent was evaporated to dryness. Residue wasmixed with 60 mL of deionized water, pH was adjusted to 1.5 with 1.0 NHCl. Insoluble was dissolved in 20 mL of DCM for wash. Aqueous solutionwas washed with more DCM (20 mL×2). The pH of aqueous was adjusted to9.5-10.0 with K₂CO₃. Insoluble was dissolved in 20 mL of DCM forextraction. Aqueous was extracted with more DCM (20 mL×3). Combined DCMextract was washed with 20 mL of saturated NaCl, dried with MgSO4,filtered, and solvent was evaporated to dryness. The residue waspurified on silica gel column to give the desired product 233 mg (22%).RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.50 min (withpurity 99.8%); LC-MS (ESI, MH⁺, free base) 369; ¹H NMR (500 MHz, CDCl₃)δ 2.59-2.72 (6H, m), 3.61 (2H, br), 3.77-3.79 (4H, t), 4.84 (2H, br),5.57-6.21 (1H, br), 7.36-7.40 (2H, m), 7.58-7.61 (1H, m).

Example 114 Preparation of Compound 168 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(diethylamino)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 168)

Preparation of2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethanol:3,6-dichloro-1,2,4-triazin-5-amine (510 mg, 3.09 mmol) was dissolved indioxane (27 mL) at room temperature. Et₃N (646 μL, 4.64 mmol) was added,following by addition of 2-(2-aminoethoxy)ethanol (616 μL, 6.18 mmol).The resulting mixture was heated in oil-bath to 85° C. (external) andthe reaction was kept at this temperature for 18 hrs. After cool down toroom temperature, the upper clear solution was decanted to another roundbottle flask. The remaining brownish oil was washed with small amount ofdioxane and decanted one more time. The combined dioxane solution wasevaporated to dryness and the residue was mixed in DCM. The productprecipitation was obtained in DCM after the solution was set inrefrigerator at 0° C. for 2 hrs. Insoluble solid product was collectedthrough filtration and the product was carefully washed with DCM×2. Asolid product was then obtained after high vacuo drying.

The DCM solution obtained from wash was combined with the above brownishresidue and evaporated to dryness. The residue was dissolved in MeOH andtransferred to Biotage samplet. The purification on silicone gel columnwas using a program 2-10% of MeOH/DCM in 20 CV. The product fractionswere identified with TLC, hplc, and confirmed by LC-MS before productfractions were combined together. Rotary evaporate the solvent and highvacuo to give the product (600 mg, 83% yield). UPLC (Agilent extendedC-18, 0.5 mL/min, 10-100% ACN in 5 min) 0.90 min; LC-MS (ESI, MH⁺)234.0+235.0 (˜35%); ¹H NMR (500 MHz, CDCl₃) δ 3.61-3.66 (4H, m),3.68-3.74 (2H, m), 3.77-3.80 (2H, m), 5.47 (1H, bs), 5.77 (1H, bs).

Preparation of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethanol:2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethanol (196 mg,0.837 mmol), 2,3-dichlorophenylboronic acid (200 mg, 1.05 mmol), cesiumcarbonate (496 mg, 1.51 mmol) were dissolved in a dioxane/water (3/1)mixture solution (20 mL). The solution was bubbled with N₂ gas for 3 minbefore Pd(PPh₃)₄(203 mg, 0.176 mmol) was added and N₂ bubbling another 2min before the reaction was heated up to 85° C. The reaction wasmonitored with HPLC and LC-MS to confirm the completeness in 2-3 hrs.The dioxane was then removed via rotary evaporation. The residue wasdissolved in MeOH and loaded on Biotage samplet directly. The siliconegel column purification was using a program 2-10% MeOH/DCM in 20 CV. Theproduct was well separated from other components and the fractions wereconfirmed with TLC, hplc, and LC-MS before the fractions were combined.A heavily oil-like product (152 mg, 53% yield) was obtained after highvacuo drying. UPLC (Agilent extended C-18, 0.5 mL/min, 10-100% ACN in 5min) 4.76 min; LC-MS (ESI, MH⁺) 344.0+346.0 (˜70%); ¹H NMR (500 MHz,CDCl₃) δ 3.65-3.66 (2H, m), 3.74-3.79 (6H, m), 7.34-7.39 (2H, m),7.58-7.60 (1H, m).

Preparation of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate:2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethanol(39.4 mg, 114 mmol) was dissolved in dioxane (2 mL) at ambienttemperature with reaction concentration at about 0.05 M. MsCl (9.75 uL,126 mmol) was added in one portion. With stirring, TEA (19 uL, 137 mmol)was dissolved in dioxane (1-2 mL) in a test tube and was added to theabove mixture solution dropwise. After addition, the reaction was keptat room temperature for 30 min and hplc shows the completeness. If thestarting material is remaining more than 5%, additional MsCl (based onthe amount of remaining alcohol) and same equivalent of TEA were addedto complete the reaction. Work up: The reaction was quenched by addingMeOH and mixture solution was evaporated to dryness. The residue wasdissolved in NaHCO₃ and extracted with DCM×3 times. Aqueous phase waschecked with LC-MS to confirm the completeness of extraction. Thecombined DCM solution was dried over Na₂SO₄ and after filtration; it wasconcentrated under reduced pressure. The residue was loaded on Biotagecolumn and purified with 2-7% MeOH/DCM in 20 CV. The UV signal shows theproduct peak and a few more fractions as a tail. TLC and hplc confirmedthe product before combine together and rotary evaporation to give acolorless solid product. High vacuo to give product (48 mg, 100% yield)and the final product was protected in N₂ and stored in refrigerator (orlow temperature). UPLC (Agilent extended C-18, 0.5 mL/min, 10-100% ACNin 5 min) 5.40 min; LC-MS (ESI, MH⁺) 422.0+424.0 (65%); ¹H NMR (500 MHz,CDCl₃) δ 3.06 (3H, s), 3.70-3.74 (4H, m), 3.78-3.79 (2H, m), 4.36-4.38(2H, m), 6.40 (1H, bs), 7.33-7.38 (2H, m), 7.56-7.58 (1H, m).

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(diethylamino)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine:2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (236 mg, 0.559 mmol) was dissolved in dioxane (10 mL).Diethyl amine (289 μL, 2.79 mmol) was added. The reaction was set up at70° C. for 2 hrs before it heated to 100° C. for overnight. Theconversion is about 44%. Another 289 uL of diethyl amine was added tocontinue the reaction for 60 hrs. The reaction was stopped by evaporatethe solvent to dryness. The residue was dissolved in 10 mL 1N HCl and 10mL Water with DCM extraction 10 mL×3. The combined DCM phase wasevaporated and residue was purified on silica gel column to give theproduct 130 mg (58.3%) yield. RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 4.40 min (with purity 99.1%); LC-MS (ESI, MH⁺, free base)399; ¹H NMR (500 MHz, CDCl₃) δ 1.00-1.03 (6H, t), 2.55-2.60 (4H, q)2.64-2.67 (2H, t), 3.57-3.60 (2H, t), 3.67 (4H, br), 5.14 (2H, br), 6.32(1H, br), 7.31-7.37 (2H, m), 7.55-7.57 (1H, m).

Example 115 Preparation of Compound 169 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(4-methylpiperazin-1-yl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 169)

2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (175 mg, 0.414 mmol) was dissolved in dioxane (8 mL)1-methylpiperazine (230 μL, 2.07 mmol) was added. The reaction was setup at 100° C. for 16 hrs. The reaction was stopped by evaporate thesolvent to dryness. The residue was dissolved in 10 mL 1N HCl and 10 mLwater with DCM extraction 10 mL×3. The combined DCM phase was evaporatedand residue was purified on silica gel column to give the product 130 mg(58.3%) yield. RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min)4.02 min (with purity 96.8%); LC-MS (ESI, MH⁺, free base) 426; ¹H NMR(500 MHz, CDCl₃) δ 2.27 (3H, s), 2.46-2.60 (10H, t), 3.61-3.64 (2H, t),3.68 (4H, br), 5.05 (2H, br), 6.34 (1H, br), 7.33-7.39 (2H, m),7.56-7.59 (1H, m).

Example 116 Preparation of Compound 170 Preparation ofN-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)methanesulfonamide(Compound 170)

Preparation ofN-(2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)-methanesulfonamide:N-(2-(2-aminoethoxy)ethyl)methanesulfonamide (437 mg, 2.4 mmol) wasdissolved in 15 mL of dioxane. TEA (1.67 mL, 12 mmol) and5-amino-3,6-dichloro-1,2,4-triazine (200 mg, 1.2 mmol). The resultingmixture was stirred at 85° C. for overnight. After cooling to roomtemperature, the solvent was evaporated to dryness. The residue waspurified on silica gel column to give the desired product 176 mg (24%yield).

Preparation ofN-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)-methanesulfonamide:(2,3-Dichlorophenyl)boronic acid (162 mg, 850 mmol),N-(2-(2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)methane-sulfinamide(176 mg, 566 mmol), cesium carbonate (369 mg, 1.13 mmol) were dissolvedin 20 ml degassed diaxane/H₂O (3:1) andtetrakis(triphenylphosphine)palladium (164 mg, 142 mmol) was added undernitrogen atmosphere. The reaction mixture was stirred at 85° C. Dioxane3 mL was added after 15 min at 85° C. A sample was checked by LC-MSafter 2 hours reaction. Solvent was evaporated to dryness at 50° C.,reduced pressure. Residue was dried in high vacuum for 2 hours. Residuewas mixed with DCM/MeOH and loaded on 25 samplet, dried in vacuum forovernight. Silica gel column purification gives the desired product 165mg (69.2% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10min) 4.72 min (with purity 97.7%); LC-MS (ESI, MH⁺, free base) 421; ¹HNMR (500 MHz, CDCl₃) δ 3.01 (3H, s), 3.34-3.36 (2H, t), 3.66-3.71 (6H,m), 5.14 (2H, br), 5.57 (1H, br), 6.20-6.27 (1H, br), 7.36-7.40 (2H, m),7.58-7.61 (1H, m).

Example 117 Preparation of Compound 171 and 172 Preparation ofN3-(2-(2-(1H-tetrazol-1-yl)ethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(Compound 171) andN3-(2-(2-(2H-tetrazol-2-yl)ethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(Compound 172)

Preparation ofN3-(2-(2-bromoethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine:2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (1.01 g, 2.37 mmol) was dissolved in 47 mL of THF.Lithium bromide (2.06 g, 23.7 mmol) was added. The reaction mixture wasstirred at 60° C. for 2 hours. A sample was checked by LC-MS. Thereaction was stopped after 3 hours at 60° C. After cooling to ambienttemperature, the insoluble was filtered, washed with DCM, and thesolvent was evaporated to dryness at reduced pressure. Residue wasdissolved in 200 mL of DCM, washed with sat NaHCO3 (2×30 ml). DCM layerwas dried with MgSO4, filtered and solvent was evaporated to dryness.Residue was dissolved in methanol and purified on silica gel column togive the desired product 608 mg (63.1% yield) after high vacuo.

N3-(2-(2-bromoethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine:(300 mg, 0.737 mmol) was dissolved in dioxane (16 mL). 90 mg of DMAP (90mg, 0.737 mmol) and 9 ml of 1H-tetrazole (51.6 mg, 0.737 mmol) wereadded. The reaction mixture was stirred at 102° C. under nitrogenatmosphere for 20 hrs. the solvent was evaporated and the residue waspurified on silica gel column to give two productN3-(2-(2-(1H-tetrazol-1-yl)ethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(40 mg, 13.7% yield) andN3-(2-(2-(2H-tetrazol-2-yl)ethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(51 mg, 17.5% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in10 min) 4.97 min (with purity 97.6%); LC-MS (ESI, MH⁺) 396; ¹H NMR (500MHz, CDCl₃) δ 3.66-3.72 (4H, m), 3.88-3.90 (2H, t), 4.63-4.66 (2H, t),4.99 (2H, br), 5.93 (1H, br), 7.36-7.40 (2H, m), 7.58-7.80 (1H, m), 8.80(1H, s); RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.95min (with purity 99.6%); LC-MS (ESI, MH⁺) 396; ¹H NMR (500 MHz, CDCl₃) δ3.63-3.70 (4H, m), 4.05-4.08 (2H, t), 4.83-4.86 (2H, t), 5.10 (2H, br),5.86 (1H, br), 7.32-7.39 (2H, m), 7.56-7.58 (1H, m), 8.52 (1H, s)

Example 118 Preparation of Compound 173 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-((2-methoxyethyl)amino)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 173)

2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (358 mg, 0.848 mmol) was mixed with 0.75 ml of2-methoxyethanamine (737 μL, 8.48 mmol). The mixture was stirred at 80°C. under nitrogen atmosphere for overnight. Solvent was evaporated todryness at reduced pressure. The residue was purified on silica gelcolumn to give the product (110 mg, 32.3% yield). RP-HPLC (betasil C18,0.5 mL/min, 10-100% ACN in 10 min) 4.53 min (with purity 95.7%); LC-MS(ESI, MH⁺) 401; ¹H NMR (500 MHz, CDCl₃) δ 2.83-2.88 (4H, m), 3.31 (3H,s), 3.50-3.53 (2H, t), 3.63-3.70 (6H, m), 5.02 (2H, br), 6.16 (1H, br),7.35-7.39 (2H, m), 7.57-7.60 (1H, m).

Example 119 Preparation of Compound 174 and 175 Preparation ofN3-(2-(2-aminoethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(Compound 174) andN-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)acetamide(Compound 175)

Preparation ofN3-(2-(2-aminoethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine:2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (300 mg, 710 mmol) was mixed with 10 mL of ACN, 10 mLof ethanol, and 30 ml of MH₃H₂O, containing 3 g of NH₄Cl. The reactionmixture was stirred at ambient temperature for 48 hours. Solvent wasevaporated to dryness at reduced pressure. Residue was mixed with 100 mLof ethanol and filtered. Combined ethanol was evaporated to dryness atreduced pressure. The product from residue was extracted with DCM (50ml×2). Combined DCM was dried over with MgSO₄, filtered, and solvent wasevaporated to dryness. Residue was dried in high vacuum for overnight togive a product (56 mg, 23% yield). RP-HPLC (betasil C18, 0.5 mL/min,1.0-100% ACN in 10 min) 4.33 min (with purity 92.5%); LC-MS (ESI, MH⁺)343; ¹H NMR (500 MHz, DMSO-d₆+D₂O) δ 3.01 (2H, br), 3.58-3.65 (4H, m),7.53-7.56 (2H, m), 7.84-7.87 (1H, m). The product was dissolved in 2 mLof 1.0 N HCl. Insoluble was filtered and filtrate was lyophilized forovernight to give the product hydrochloride salt.

Preparation ofN-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)acetamide:N3-(2-(2-aminoethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine:(42 mg, 122 mmol) was dissolved in dioxane (5 mL), TEA (34.1 μL, 245mmol) was added. Acetic anhydride (12.1 μL, 128 mmol) was added. Thereaction solution was stirred at ambient temperature for 15 min. Asample was checked by LC-MS, showed the reaction was over. 20 μl ofBuNH₂ was added to quench the excess of acetic anhydride. Solvent wasevaporated to dryness at reduced pressure. Residue was purified onsilica gel column to give the product (34 mg, 72.1% yield). RP-HPLC(betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.72 min (with purity98.0%); LC-MS (ESI, MH⁺) 385; ¹H NMR (500 MHz, CDCl₃) δ 2.04 (3H, s),2.10 (1H, s), 3.47-50 (2H, m), 3.58-3.61 (2H, t), 3.68 (4H, br), 5.10(2H, br), 6.61 (1H, br), 7.30-7.39 (2H, m), 7.60-7.63 (1H, m).

Example 120 Preparation of Compound 176 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(methylsulfonyl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 176)

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(methylthio)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine:2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (200 mg, 0.474 mmol) and sodium methanethiolate (100mg, 1.42 mmol) were mixed in methanol (20 mL) and stirred at ambienttemperature. The reaction solution was concentrated and the residue wassubject to flash chromatography to give a product 72 mg (75% pure, 25%fragment). LC-MS [ESI-MH⁺]: m/z 373.

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(methylsulfonyl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine:The methylsulfide starting material (40 mg, 0.107 mmol, 75% purity) wasdissolved in MeOH (4 mL). A solution of oxone in water (2 mL) was addedto the above solution at 0° C. to form a suspension. The mixture wasstirred at ambient temperature for overnight. 30% of sulfoxide and 70%sulfone were generated. Additional 20 mg of oxone was added. After 3hrs, reaction was completed. The residue was subjected to reversed-phasechromatography. Desired fractions were collected and concentrated. Finalwater solution was lyophilized to dryness to give a product as whitefoaming powder (48 mg, 99% purity, 84% yield). LC-MS [ESI-MH⁺]: m/z 406.¹H-NMR (DMSO-d6) δ ppm: 3.063 (s, 3H), 3.351 (d, J=5.0 Hz, 2H),3.676-3.751 (m, 4H), 3.981 (d, 2H), 6.372 (s, 1H), 7.355 (d, J=6.5 Hz,1H), 7.442 (dd, J=8.0 Hz, J₂=7.5 Hz, 1H), 7.700 (d, J=6.5 Hz, 1H).

Example 121 Preparation of Compound 177 Preparation of6-(2,3-dichlorophenyl)-N3-(3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl)-1,2,4-triazine-3,5-diamine(Compound 177)

Preparation of 3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropan-1-amine:3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl methanesulfonate (500 mg,1.85 mmol) was mixed with 10 ml of ethanol, 50 ml of NH₄OH (containing10% of NH₄Cl). The mixture was stirred at ambient temperature for 2days. Solid NaCl was added to 15%. Desired product was extracted withDCM (30 ml×5). Combined DCM was dried with MgSO₄, filtered, and solventwas evaporated to dryness. Residue was dried in vacuum for overnight togive the product mixture 424 mg (>100% yield).

Preparation of6-chloro-N3-(3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl)-1,2,4-triazine-3,5-diamine:3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropan-1-amine (132 mg, 690 mmo)and 5-Amino-3,6-dichloro-1,2,4-triazine (114 mg, 0.69 mmol) weredissolved in dioxane (15 mL) at room temperature. Et₃N (0.192 mL, 1.38mmol) was added. The resulting mixture was stirred at 95° C. undernitrogen atmosphere for overnight. After cooling to room temperature,the solvent was evaporated to dryness. The residue was purified onsilica gel column to give the product 104 mg (47.1 yield).

Preparation of6-(2,3-dichlorophenyl)-N3-(3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl)-1,2,4-triazine-3,5-diamine:(2,3-dichlorophenyl)boronic acid (93 mg, 0.488 mmol),6-chloro-N3-(3-(2-(2-methoxyethoxy)ethoxy)-2-methylpropyl)-1,2,4-triazine-3,5-diamine(104 mg, 0.325 mmol), cesium carbonate (212 mg, 0.650 mmol) weredissolved in 20 mL degassed diaxane/H2O (3:1.) andtetrakis(triphenylphosphine)palladium (94 mg, 0.081 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.Solvent was evaporated to dryness at 50° C., reduced pressure. Residuewas purified on silica gel column to give the product 55 mg (39.3%yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 6.02min (with purity 96.3%); LC-MS (ESI, MH⁺) 430; ¹H NMR (500 MHz, CDCl₃) δ1.00-1.03 (3H, d), 2.12 (1H, br), 3.34 (4H, br), 3.48-3.70 (8H, m),3.71-3.74 (4H, m), 5.10 (2H, br), 6.61 (1H, br), 7.30-7.39 (2H, m),7.60-7.62 (1H, m).

Example 122 Preparation of Compound 178 Preparation of2-((2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)amino)aceticacid (Compound 178)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (100 mg, 0.237 mmol), glycine (356 mg, 4.74 mmol), andNaHCO3 (60 mg, 710 mmol) were dissolved in a 6 mL acetonitrile/water(1:1) solution. The mixture was heated over 100° C. in an oil bath for 2days. After concentration, the product was purified on C18 column toyield product as white solid (36 mg, 96% purity, 37.9% yield). LC-MS[ESI-MH⁺]: m/z 400. ¹H-NMR (DMSO-d6) δ ppm: 7.698 (d, J=5.5 Hz, 1H),7.441 (t, J=8 Hz, 1H), 7.352 (d, J=8 Hz, 1H), 7.20-6.35 (b, 2H), 4.640(t, J=6.0 Hz, 1H), 4.534 (quintet, J₁=11 Hz, J₂=5.5 Hz, J₃=5.5 Hz, 1H),4.396 (dd, J₁=5.5 Hz, J₂=6.5 Hz, 1H), 3.540-3.440 (m, 12H).

Example 123 Preparation of Compound 179 Preparation of(S)-2-((2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)amino)-3-methylbutanoicacid (Compound 179)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (100 mg, 0.059 mmol), L-valine (555 mg, 1.184 mmol) andsodium bicarbonate (60 mg, 0.178 mmol) were added into a mixture solventof acetonitrile (5 mL) and deionized water (5 mL). The mixture washeated over 100° C. for overnight. Solvent was removed under reducedpressure. Residue was subjected to reversed phase purification to yieldproduct as white solid (31 mg, 97% purity, 29.5% yield). LC-MS[ESI-MH⁺]: m/z 443. ¹H-NMR (DMSO-d6) δ ppm: 7.689 (d, J=1.5 Hz, 1H),7.437 (t, J=8 Hz, 1H), 7.357 (dd, J₁=1.5 Hz, J₂=7.5 Hz, 1H), 7.20-6.35(b, 2H), 4.100-4.200 (b, 2H), 3.522-3.428 (m, 6H), 2.781 (t, J=6.0 Hz,1H), 1.849 (m, 1H), 1.776 (s, 1H), 0.853 (d, J=7.0 Hz, 1H), 0.802 (d,J=6.5 Hz, 1H).

Example 124 Preparation of Compound 180 Preparation of6-(2,3-dichlorophenyl)-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine(Compound 180)

Preparation of10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-amine:10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-ylmethanesulfonate (500 mg, 1.195 mmol) was mixed with 10 mL of ethanol,75 mL of NH₄OH (containing 10% of NH₄Cl). The mixture was stirred atambient temperature for 2 days. Solid NaCl (about 8 g) was added tosolution and the desired product was extracted with DCM (30 mL×4).Combined DCM extract was dried with MgSO₄, filtered, and solvent wasevaporated to dryness. Residue was dried in vacuum for overnight to givethe product 387 mg (95% yield).

Preparation of6-chloro-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine:10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-amine(387 mg, 1.14 mmol) and 5-Amino-3,6-dichloro-1,2,4-triazine (157 mg,0.95 mmol) were dissolved in dioxane (20 mL) at room temperature. Et₃N(0.265 mL, 1.9 mmol) was added. The resulting mixture was stirred at 95°C. under nitrogen atmosphere for overnight. Solvent was evaporated todryness. The residue was purified on silica gel column to the product353 mg (79% yield).

Preparation of6-(2,3-dichlorophenyl)-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine:(2,3-dichlorophenyl)boronic acid (216 mg, 1.132 mmol),6-chloro-N3-(10-((2-(2-methoxyethoxy)ethoxy)methyl)-2,5,8,11-tetraoxatridecan-13-yl)-1,2,4-triazine-3,5-diamine(353 mg, 0.754 mmol), cesium carbonate (492 mg, 1.51 mmol) weredissolved in 30 mL degassed mixture of diaxane/H₂O (3:1) andtetrakis(triphenylphosphine)palladium (218 mg, 0.189 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.for overnight. Solvent was evaporated to dryness at 50° C. under thereduced pressure. Residue was purified on silica gel column to give theproduct 286 mg (65.5% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 6.36 min (with purity 95.3%); LC-MS (ESI, MH⁺) 578; ¹HNMR (500 MHz, CDCl₃) δ 3.36 (6H, s), 3.54-3.80 (22H, m), 3.80 (1H, br),3.84-3.86 (2H, t), 5.10 (2H, br), 6.61 (1H, br), 7.34-7.39 (2H, m),7.56-7.60 (1H, m).

Example 125 Preparation of Compound 181 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(2-(oxetan-3-yloxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 181)

To a solution of2-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethoxy)ethanol(800 mg, 0.506 mmol) in DMF (20 mL) was added 3-iodo-oxetane (298 mg,1.62 mmol). NaH (810 mg, 60% dispersion in mineral oil, 20.26 mmol) wasadded to the above solution. The mixture was stirred at ambienttemperature for 1 h. Additional 300 mg and 400 mg of NaH (60% dispersionin mineral oil) were added consecutively. After 3 h, 27% conversion wasobserved. Solid was filtered off and washed with, dioxane. Filtrate wasconcentrated on RotaVap under reduced pressure. The residue was purifiedon silica gel column to afford 50 mg product (5.6% yield) as lightyellow solid (95.5% purity). LC-MS [ESI-MH⁺]: m/z 444. ¹H-NMR (DMSO-d6)δ ppm: 7.698 (d, J=5.5 Hz, 1H), 7.441 (t, J=8 Hz, 1H), 7.352 (d, J=8 Hz,1H), 7.20-6.35 (b, 2H), 4.640 (t, J=6.0 Hz, 1H), 4.534 (quintet, J₁=11Hz, J₂=5.5 Hz, J₃=5.5 Hz, 1H), 4.396 (dd, J₁=5.5 Hz, J₂=6.5 Hz, 1H),3.540-3.440 (m, 12H).

Example 126 Preparation of Compound 182 Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-1-ol(Compound 182)

Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propan-1-ol:5-Amino-3,6-dichloro-1,2,4-triazine (1.5 g, 9.09 mmol) was dissolved indioxane (60 mL) at room temperature. Et₃N (1.9 mL, 13.64 mmol) wasadded, followed by addition of 2-aminopropan-1-ol (1.37 g, 18.2 mmol).The resulting mixture was stirred at 95° C. for overnight. Solvent wasevaporated to dryness at reduced pressure. Residue was purified onsilica gel column to give the product 1.93 g (>100% yield).

Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-1-ol:(2,3-dichlorophenyl)boronic acid (1.93 g, 10.1 mmol),2-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)propan-1-ol (1.37 g, 6.73mmol), cesium carbonate (4.4 g, 13.5 mmol) were dissolved in 150 mLdegassed mixture of dioxane/H₂O (3:1) andtetrakis(triphenylphosphine)palladium (1.94 g, 1.68 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.for 4 hours. Insoluble was filtered and solvent was evaporated todryness at 50° C., reduced pressure. residue was dried in vacuum forovernight and purified on silica gel column to give the product 1.54 g(72.9% yield) after high vacuo. RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 6.36 min (with purity 95.3%); LC-MS (ESI, MH⁺)578; ¹H NMR (500 MHz, CDCl₃) δ 3.36 (6H, s), 3.54-3.80 (22H, m), 3.80(1H, br), 3.84-3.86 (2H, t), 5.10 (2H, br), 6.61 (1H, br), 7.34-7.39(2H, m), 7.56-7.60 (1H, m).

Example 127 Preparation of Compound 183 Preparation of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethyl carbonate (Compound 183)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethanol(200 mg, 0.581 mmol), and bis(4-nitrophenyl) carbonate (194 mg, 0.639mmol), DMAP (7.1 mg, 0.058 mmol), and TEA (50 μL, 360 mmol) were mixedin dioxane (20 mL). Solvent was removed and residue was dried overvacuum overnight, affording sticky yellow residue. The residue wasdissolved in 30 mL DCM and washed with 0.1 N monobasic phosphate. DCMphase was dried over Na₂SO₄ and solid was filtered off. Concentrationgave yellow foaming residue, which was further dried under high vacuoovernight. Yield product as yellow foaming solid (140 mg, 51% purity).The above product mixture (140 mg, 0.137 mmol), methanol (557 μL, 13.74mmol), and DMAP (16.8 mg, 0.137 mmol) were mixed. The mixture wasstirred under N₂ atmosphere at ambient temperature. Solvent was removedand the residue was subject to flash chromatography purification toyield product as off-white solid (40 mg, 96.8% purity, 52.5% yield).LC-MS [ESI-MH⁺]: m/z 402. ¹H-NMR (DMSO-d6) δ ppm: 3.554 (t, J=4.5 Hz,2H), 3.565 (s, 2H), 3.637 (t, J=4.5 Hz, 2H), 3.697 (s, 3H), 4.203 (t,J=4.5 Hz, 2H), 7.355 (d, J=6.5 Hz, 1H), 7.442 (dd, J_(1=8.0) Hz, J₂=7.5Hz, 1H), 7.700 (d, J=6.5 Hz, 1H).

Example 128 Preparation of Compound 184 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(piperazin-1-yl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine.3HCl(Compound 184)

Preparation of tert-butyl4-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)piperazine-1-carboxylate:N3-(2-(2-bromoethoxy)ethyl)-6-(2,3-dichlorophenyl)-1,2,4-triazine-3,5-diamine(50 mg, 123 mmol) was dissolved in 5 mL of dioxane. tert-Butylpiperazine-1-carboxylate (46 mg, 246 mmol) and DMAP (7.50 mg, 0.061mmol) were added. The reaction mixture was stirred at 95° C. forovernight. The solvent was evaporated to dryness. The residue waspurified on silica gel column to give product 38 mg (60.4% yield).

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(piperazin-1-yl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine.3HCl:tert-Butyl4-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)piperazine-1-carboxylate(61 mg, 0.119 mmo) was dissolved in 2 mL of Methanol and 2 ml of HCl (4Min dioxane) and stirred at ambient temperature for 1 hour. Solvent wasevaporated to dryness, residue was dried in vacuum for overnight to givea product 60 mg (97% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 4.25 min (with purity 97.7%); LC-MS (ESI, MH⁺) 412; ¹HNMR (500 MHz, D₂O) δ 3.57-3.66 (10H, m), 3.72-3.76 (4H, br), 3.92 (2H,br), 7.33-7.40 (2H, m), 7.66-7.68 (1H, m).

Example 129 Preparation of Compound 185 Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethanol-HCl(Compound 185)

Preparation of2-((5-amino-6-chloro-1,2,4-triazin-3-yl)(methyl)amino)ethanol:5-Amino-3,6-dichloro-1,2,4-triazine (366 mg, 2.22 mmol) and2-(methylamino)ethanol (213 μL, 2.66 mmol) were dissolved in dioxane (25mL) at room temperature. Et₃N (0.62 mL, 4.44 mmol) was added. Themixture was stirred at 90° C. for overnight. Solvent was evaporated todryness, residue was redissolved in DCM (20 mL), insoluble was collectedand dried in vacuum for 3 hours to give the product 392 mg (87% yield).

Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethanol:(2,3-dichlorophenyl)boronic acid (410 mg, 2.15 mmol),2-((5-amino-6-chloro-1,2,4-triazin-3-yl)(methyl)amino)ethanol (292 mg,1.43 mmol), cesium carbonate (934 mg, 2.87 mmol) were dissolved in 30 mLdegassed dioxane/H₂O (3:1) and tetrakis(triphenylphosphine)palladium(934 mg, 2.87 mmol) was added under nitrogen atmosphere. The reactionmixture was stirred at 90° C. for 2 hours. Solvent was evaporated todryness and residue was purified on silica gel column to give thedesired product 320 mg (71% yield). RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 4.55 min (with purity 95.8%); LC-MS (ESI, MH⁺)314; ¹H NMR (500 MHz, DMSO-d₆) δ 3.22 (3H, s), 3.66-3.72 (4H, m),7.53-7.57 (2H, m), 7.84-7.87 (1H, m), 8.25 (1H, br), 9.23 (1H, br). Theproduct was dissolved in 2 mL of 1.0 N HCl. Insoluble was filtered andfiltrate was lyophilized for overnight to give the product hydrochloridesalt.

Example 130 Preparation of Compound 186 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-((2-methoxyethyl)sulfonyl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 186)

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-((2-methoxyethyl)thio)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine:The solution of sodium 2-methoxythioethoxide (21.8 mg, 0.237 mmol) andKOtBu (0.237 mL, 1M, 0.237 mmol) in tBuOH were added to a solution of2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (100 mg, 0.237 mmol) in DMF (1 mL). The mixture wasstirred at RT under N₂ atmosphere. After 2 hrs, reaction was completed.Solvent was removed under reduced pressure. The residue was purified onsilica gel column to yield 30 mg white solid (84% purity). LC-MS[ESI-MH⁺]: m/z 418; ¹H NMR (500 MHz, DMSO-d₆) δ ppm: 2.691 (t, J=6.5 Hz,2H), 3.236 (s, 3H), 3.467 (m, 4H), 3.560 (m, 4H), 6.600-7.250 (b, 2H),7.352 (q, J₁=1.5 Hz, J₂=7.5 Hz, 1H), 7.443 (t, J=6 Hz, 1H), 7.572 (d,J=6 Hz, 1H).

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-((2-methoxyethyl)sulfonyl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine:The6-(2,3-dichlorophenyl)-N3-(2-(2-((2-methoxyethyl)thio)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(43 mg, 0.090 mmol, 88% purity) was dissolved in MeOH (1 mL). A solutionof oxone (83 mg, 0.271 mmol) in water (1 mL) was added to the abovesolution at 0° C. to form a suspension. The mixture was stirred at roomtemperature for overnight. The product mixture was purified on silicagel column to give product as yellow solid (40 mg, 95% purity, 97.3%yield). LC-MS [ESI-MH⁺]: m/z 450; ¹H NMR (500 MHz, DMSO-d6) δ ppm: 3.251(s, 3H), 3.376 (m, 4H), 3.458 (b, 2H), 3.571 (t, J=6 Hz, 2H), 3.685 (t,J=6 Hz, 2H), 3.800 (t, J=6 Hz, 2H), 6.600-7.250 (b, 2H), 7.351 (q,J₁=1.5 Hz, J₂=7.5 Hz, 1H), 7.444 (t, J=6 Hz, 1H), 7.694 (d, J=6 Hz, 1H).

Example 131 Preparation of Compound 187 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(methylsulfinyl)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 187)

The6-(2,3-dichlorophenyl)-N3-(2-(2-(methylthio)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(50 mg, 0.134 mmol, 96% purity) was dissolved in MeOH (1 mL). A solutionof oxone (39.4 mg, 0.128 mmol) in water (1 mL) was added dropwise to theabove solution at 0° C. to form a suspension. The addition was finishedin half an hour. The mixture was stirred at 0° C. for 3 h. LC-MSanalysis showed that the reaction to sulfoxide was completed. Solventwas removed under reduced pressure and residue was loaded to a silicagel column to give the product as light-yellow solid (50 mg, 96% purity,100% yield). LC-MS [ESI-MH⁺]: m/z 390; ¹H-NMR (DMSO-d6) δ ppm: 2.564 (s,3H), 2.848 (m, 1H), 3.038 (m, 1H), 3.164 (d, J=5.0 Hz, 2H), 3.453 (br,2H), 3.571 (t, J=6.0 Hz, 2H), 3.777 (m, 2H), 4.108 (m, 1H), 6.500-7.300(br, 2H), 7.355 (d, J=6.5 Hz, 1H), 7.442 (dd, J₁=8.0 Hz, J₂=7.5 Hz, 1H),7.700 (d, J=6.5 Hz, 1H).

Example 132 Preparation of Compound 188 Preparation of6-(2,3-dichlorophenyl)-N3-(1-(2-(2-methoxyethoxy)ethoxy)propan-2-yl)-1,2,4-triazine-3,5-diamine.HCl(Compound 188)

2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-1-ol(198 mg, 0.631 mmol) was dissolved in 10 mL of dioxane. NaH (252 mg,6.31 mmol) was added, then 3 mL of DMF was added. After stirring atambient temperature for 10 min, 2-(2-methoxyethoxy)ethylmethanesulfonate (100 mg, 0.504 mmol) in 2 mL of dioxane was added. Themixture was stirred at 80° C. for 1.5 hours, and the residue wasdissolved in 30 mL deionized water. Solid NaCl was added to 10% and pHwas adjusted to about 11.0. Desired product was extracted with DCM (15mL×3). Combined DCM was dried with MgSO₄, filtered and solvent wasevaporated to dryness. Residue was dried in vacuum and purified onsilica gel column to give the product 40 mg (15.2% yield). RP-HPLC(betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 5.60 min (with purity90.4%); LC-MS (ESI, MH⁺) 416; ¹H NMR (500 MHz, DMSO-d₆) δ 1.18-1.20 (3H,d), 3.23 (3H, s), 3.42-3.57 (10H, m), 4.19 (1H, br) 7.53-7.57 (2H, m),7.84-7.87 (1H, m), 8.25 (1H, br), 9.23 (1H, br). The product wasdissolved in 2 mL of 1.0 N HCl. Insoluble was filtered and filtrate waslyophilized for overnight to give the product hydrochloride salt.

Example 133 Preparation of Compound 189 Preparation of6-(2,3-dichlorophenyl)-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine(Compound 189)

Preparation of6-chloro-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine:5-Amino-3,6-dichloro-1,2,4-triazine (200 mg, 1.212 mmol) was dissolvedin dioxane (30 mL) at room temperature. Et₃N (0.17 mL, 1.21 mmol) wasadded, followed by addition of N1,N2-dimethylethane-1,2-diamine (1.28 g,14.55 mmol) in 1 ml of dioxane. The resulting mixture was stirred at 95°C. for 1 hour. A sample was checked by LC-MS and showed the reaction wasover. Solvent was evaporated to dryness, residue was mixed with 50 mL ofhexane and liquid was decanted, precipitate was dried in high vacuum forovernight to give the product 338 mg (>100% yield).

Preparation of6-(2,3-dichlorophenyl)-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine:(2,3-dichlorophenyl)boronic acid (347 mg, 1.82 mmol),6-chloro-N3-methyl-N3-(2-(methyl amino)ethyl)-1,2,4-triazine-3,5-diamine(1.212 mmol, 263 mmol), cesium carbonate (790 mg, 2.42 mmol) weredissolved in 30 mL degassed dioxane/H₂O (3:1) andtetrakis(triphenylphosphine)palladium (350 mg, 0.303 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.for 1.5 hour. Solvent was evaporated to dryness at 50° C. under thereduced pressure. Residue was mixed with DCM/MeOH and insoluble wasfiltered and concentrated. Reside was purified on silica gel column togive product 277 mg (69.8% yield). RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 3.97 min (with purity 98.0%); LC-MS (ESI, MH⁺)327; ¹H NMR (500 MHz, D₂O) δ 2.77 (3H, s), 3.26 (3H, s), 3.38-3.41 (2H,t), 4.00-4.09 (2H, m), 7.45-7.52 (2H, m), 7.78-7.80 (1H, m). The wasdissolved in 2 mL of DCM, 0.63 mL of 1.0 M HCl in diethyl ether wasadded. The mixture was stirred at r.t. for 1 hour. Solvent wasevaporated to dryness and high vacuo to give the product ashydrochloride salt.

Example 134 Preparation of Compound 190 Preparation ofN-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)-2-(2-methoxyethoxy)-N-methylacetamide(Compound 190)

2-(2-Methoxyethoxy)acetic acid (44.3 mg, 0.330 mmol) and HOBT (37.2 mg,0.275 mmol) were dissolved in 20 mL of anhydrous DCM. DCC (85 mg, 0.413mmol) was added. The reaction mixture was stirred at ambient temperaturefor 30 minutes, then mixed with 90 mg of6-(2,3-dichlorophenyl)-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine(90 mg, 0.275 mmol). The reaction mixture was stirred at ambienttemperature under nitrogen atmosphere for overnight. Insoluble wasfiltered off and filtrate was concentrated at reduced pressure. Residuewas dissolved in 20 ml of deionized water, pH was adjusted to 2.0 with1.0 N HCl. Insoluble was filtered and aqueous was washed with DCM (20mL×2). NaCl was added to make 15% and pH was readjusted to 12.3 withNaOH. Desired product was extracted with DCM (20 mL×4). Combined DCMextract was dried with MgSO4, filtered and solvent was evaporated todryness. Residue was purified on silica gel column to give product 71 mg(58.2% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min)4.85 min (with purity 99.8%); LC-MS (ESI, MH⁺, free base) 443; ¹H NMR(500 MHz, D₂O) δ 3.00 (3H, s), 3.24 (3H, s), 3.34 (3H, s), 3.60-3.77(6H, m), 3.77 (2H, br), 4.18-4.30 (2H, m), 7.45-7.52 (2H, m), 7.78-7.80(1H, m). The product was dissolved in 1.0 N HCl. Insoluble was filteredand filtrate was lyophilized for overnight to give the producthydrochloride salt.

Example 135 Preparation of Compound 191 Preparation of2-((2-(2-((6-amino-5-(2,3-dichlorophenyl)pyrazin-2-yl)amino)ethoxy)ethyl)-(methyl)amino)acetamide(Compound 191)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (190 mg, 73% purity, 0.328 mmol), N-methyl glycinamide(868 mg, 9.85 mmol) and sodium bicarbonate (83 mg, 0.985 mmol) wereadded to a mixture of acetonitrile (10 mL) and deionized water (10 mL).The mixture was heated over 100° C. overnight. The product mixture waspurified on silica gel column to give product as white powder (32 mg,purity 94.5%, yield 23.6%). LC-MS [ESI-MH⁺]: m/z 415. ¹H-NMR (DMSO-d₆) δppm: 2.256 (s, 3H), 2.784 (br, 1H), 3.038 (m, 1H), 3.163 (d, J=5.0 Hz,2H), 3.417 (br, 2H), 3.487 (m, 4H), 6.500-7.300 (br, 2H), 7.355 (d,J=6.5 Hz, 1H), 7.442 (dd, J₁=8.0 Hz, J₂=7.5 Hz, 1H), 7.700 (d, J=6.5 Hz,1H).

Example 136 Preparation of Compound 192 Preparation of2-(2-amino-2-oxoethoxy)-N-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)(methyl)amino)ethyl)-N-methylacetamide(Compound 192)

2-(2-Amino-2-oxoethoxy)acetic acid (43.9 mg, 0.330 mmol) and HOBT (24.8mg, 18.3 mmol) were dissolved in anhydrous dioxane (15 mL), DCC (68.1mg, 0.330 mmol) was added. The reaction mixture was stirred at ambienttemperature for 30 minutes, then mixed with6-(2,3-dichlorophenyl)-N3-methyl-N3-(2-(methylamino)ethyl)-1,2,4-triazine-3,5-diamine(60 mg, 0.183 mmol). The reaction mixture was stirred at ambienttemperature under nitrogen atmosphere for overnight. Insoluble wasfiltered off and filtrate was concentrated at reduced pressure. Residuewas dissolved in 20 mL of deionized water, pH was adjusted to 2.0 with1.0 N HCl. Insoluble was filtered and aqueous was washed with DCM (20ml×2). Solid NaCl was added to make 15% and pH was readjusted to 12.3with NaOH. Desired product was extracted with DCM (20 mL×4). CombinedDCM extraction was dried with MgSO₄, filtered, and solvent wasevaporated to dryness. Residue was purified on silica gel column to givethe product 48.2 mg (59.2% yield). RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 4.43 min (with purity 97.5%); LC-MS (ESI, MH⁺)442; ¹H NMR (500 MHz, D₂O) δ 2.96 (3H, s), 3.19 (3H, s), 3.57-3.75 (4H,m), 3.98.4.02 (2H, m), 4.23-4.30 (2H, m), 7.45-7.52 (2H, m), 7.78-7.80(1H, m). The product was dissolved in 1.0 N HCl. Insoluble was filteredand filtrate was lyophilized for overnight to give the producthydrochloride salt.

Example 137 Preparation of Compound 193 Preparation of6-(2,3-dichlorophenyl)-N3-(2-((2-(2-methoxyethoxy)ethyl)(methyl)amino)ethyl)-N3-methyl-1,2,4-triazine-3,5-diamine(Compound 193)

Preparation ofN1-(2-(2-methoxyethoxy)ethyl)-N1,N2-dimethylethane-1,2-diamine:2-(2-Methoxyethoxy)ethyl methanesulfonate (400 mg, 2.02 mmol) and 1.8 gof N1,N2-dimethylethane-1,2-diamine (1.8 g, 20.2 mmol) were dissolved in20 mL of dioxane. The reaction mixture was stirred at 90° C. forovernight. Solvent was evaporated to dryness, residue was dried in highvacuum for overnight to give a product 380 mg (99% yield).

Preparation of6-(2,3-dichlorophenyl)-N3-(2-((2-(2-methoxy-ethoxy)ethyl)(methyl)amino)ethyl)-N3-methyl-1,2,4-triazine-3,5-diamine:5-Amino-3,6-dichloro-1,2,4-triazine (300 mg, 1.09 mmol) was dissolved indioxane (30 ml) at room temperature.N1-(2-(2-methoxyethoxy)ethyl)-N1,N2-dimethylethane-1,2-diamine (380 mg,2.0 mmol) and TEA (0.464 mL, 3.33 mmol) were added. The resultingmixture was stirred at 90° C. for overnight. The mixture directly goesto next step after adding 10 mL of deionized water.(2,3-Dichlorophenyl)boronic acid (429 mg, 2.25 mmol), cesium carbonate(0.98 mg, 3.00 mmol) were dissolved in mixture of6-chloro-N3-(2-((2-(2-methoxyethoxy)ethyl)(methyl)amino)ethyl)-N3-methyl-1,2,4-triazine-3,5-diamine.The mixture was purged with N₂ for 10 min andtetrakis(triphenylphosphine)palladium (433 mg, 0.375 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 90° C.for 1 hour. After cooling to room temperature, insoluble was filteredand filtrate was concentrated to dryness at 50° C., reduced pressure.Residue was dissolved in 50 mL of deionized water. pH was readjusted to2.0 with 1.0 N HCl, washed with DCM (20 ml×3). Aqueous was checked byLC-MS, then adjusted to pH 12.5 with NaOH, NaCl was added to about 15%.and desired product was extracted with DCM (20 mL×4). Combined DCM wasdried with MgSO₄, filtered and solvent was evaporated to dryness.Residue was purified on silica gel column to give the product 308 mg(47.8% yield) after high vacuo drying. RP-HPLC (betasil C18, 0.5 mL/min,10-100% ACN in 10 min) 4.41 min (with purity 96.6%); LC-MS (ESI, MH⁺)429; ¹H NMR (500 MHz, D₂O) δ 3.00 (3H, s), 3.26 (3H, s), 3.34 (3H, s),3.58-3.70 (8H, m), 3.84-3.87 (2H, t), 4.15 (2H, br), 7.45-7.52 (2H, m),7.78-7.80 (1H, m). The product was dissolved in 1.0 N HCl. Insoluble wasfiltered and filtrate was lyophilized for overnight to give the producthydrochloride salt.

Example 138 Preparation of Compound 194 Preparation of2-((2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)amino)acetamide(Compound 194)

2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethylmethanesulfonate (220 mg, 0.260 mmol), 2-aminoacetamide hydrochloride(288 mg, 2.60 mmol) and sodium bicarbonate (1.09 g, 13.02 mmol) wereadded to a mixture of acetonitrile (20 mL) and deionized water (20 mL).The mixture was heated over 100° C. in an oil bath for overnight. Theproduct mixture was purified on silica gel column to give product aswhite powder (14 mg, yield 13.4%). LC-MS [ESI-MH⁺]: m/z 400; ¹H-NMR(CDCl₃) δ ppm: 7.582 (m, 1H), 7.437 (t, J=8 Hz, 1H), 7.370 (m, 2H),5.577 (br, 2H), 4.888 (br, 2H), 3.681 (br, 4H), 3.615 (t, J=5.0 Hz, 2H),3.372 (s, 2H), 2.880 (t, J=5.0 Hz, 2H).

Example 139 Preparation of Compound 195 Preparation of1-amino-3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-2-ol.HCl(Compound 195)

Preparation of tert-butyl(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-hydroxypropyl)carbamate:5-Amino-3,6-dichloro-1,2,4-triazine (300 mg, 1.82 mmol) was dissolved indioxane (30 ml) at room temperature. tert-Butyl(3-amino-2-hydroxypropyl)carbamate (450 mg, 2.36 mmol) and TEA (507 μL,3.64 mmol) were added. The resulting mixture was stirred at 90° C. forovernight. Insoluble was filtered and filtrate was concentrated atreduced pressure. Residue was purified on silica gel column product 474mg (82% yield).

Preparation of1-amino-3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-2-ol:(2,3-dichlorophenyl)boronic acid (234 mg, 1.23 mmol), tert-butyl(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)-2-hydroxypropyl)carbamate(261 mg, 0.819 mmol), cesium carbonate (534 mg, 1.64 mmol) weredissolved in 30 mL degassed dioxane/H2O (3:1) andtetrakis(triphenylphosphine)palladium (237 mg, 0.205 mmol) was addedunder nitrogen atmosphere. The reaction mixture was stirred at 85° C.for 2 hours. Solvent was evaporated to dryness at 50° C. under thereduced pressure. Residue was purified on silica gel column to giveproduct 243 mg (69.1% yield). The product was mixed with 15 mL of 4.0NHCl in dioxane and 5 ml of methanol, stirred at r.t. for 2 hour. Solventwas evaporated to dryness. Residue was dried in high vacuum overnight togive the final product as hydrochloride salt. RP-HPLC (betasil C18, 0.5mL/min, 10-100% ACN in 10 min) 4.09 min (with purity 99.8%); LC-MS (ESI,MH⁺) 329; ¹H NMR (500 MHz, D₂O) δ 2.87-2.93 (1H, m), 2.92-3.15 (1H, d),3.52-3.70 (2H, m), 4.13 (1H, br), 7.45-7.52 (2H, m), 7.78-7.80 (1H, m).

Example 140 Preparation of Compound 196 Preparation ofN-(3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-hydroxypropyl)-2-(2-methoxyethoxy)acetamide(Compound 196)

2-(2-Methoxyethoxy)acetic acid (48.9 mg, 0.365 mmol) and HOBT (40.1 mg,0.304 mmol) were dissolved in 10 mL of anhydrous DCM. DCC (94 mg, 0.456mmol) was added. The reaction mixture was stirred at ambient temperaturefor 30 minutes, then mixed with1-amino-3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-2-ol(100 mg, 0.304 mmol) and TEA (93 uL, 0.668 mmol) in 10 mL of anhydrousacetonitrile. The reaction mixture was stirred at ambient temperatureunder nitrogen atmosphere for 2 hours. A sample was checked by LC-MS,showed that reaction was over. Solvent was evaporated to dryness atreduced pressure, residue was dried in vacuum for overnight. Residue wasdissolved in 15 mL of MeOH, 5 mL of 1.0 N NaOH was added, stirred atroom temperature for 30 min. pH was readjusted to 2.0 with 1.0 N HCl.Insoluble was filtrated and filtrate was concentrated at reducedpressure to almost dryness. Residue was dissolved 20 ml of deionizedwater, pH was adjusted to 2.0 with 1.0 N HCl aqueous, washed with DCM(20 mL×2). Aqueous was adjusted to pH 12.5 with NaOH, stirred for 30minutes. Solid NaCl was added to about 15%. and desired product wasextracted with DCM (20 mL×4). Combined DCM was dried with MgSO₄,filtered and solvent was evaporated to dryness. Residue was dried invacuum for overnight to give the final product 76 mg (56.2% yield).RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.86 min (withpurity 96.9%); LC-MS (ESI, MH⁺, free base) 445; ¹H NMR (500 MHz, D₂O) δ3.22-3.27 (2H, m), 3.28 (3H, s), 3.34-3.44 (3H, m), 3.53-3.55 (2H, t)3.62-3.64 (2H, t), 3.94 (1H, br), 3.98 (2H, s), 7.34-7.41 (2H, m),7.66-7.69 (1H, m). The product was dissolved in 1.0 N HCl. Insoluble wasfiltered and filtrate was lyophilized for overnight to give the producthydrochloride salt.

Example 141 Preparation of Compound 197 Preparation of methyl2-(2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethoxy)acetate(Compound 197)

2-(2-(2-((5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethoxy)acetic(5 mg) was dissolved in 0.5 mL of MeOH, 0.07 mL of 1.0 M HCl in etherwas added. The mixture was stirred at room temperature for 1 hour.Solvent was evaporated to dryness, residue was dried in high vacuum forovernight to give the product 5.0 mg (100% yield). RP-HPLC (betasil C18,0.5 mL/min, 10-100% ACN in 10 min) 5.32 min (with purity 94.8%); LC-MS(ESI, MH⁺) 416; ¹H NMR: N/A

Example 142 Preparation of Compound 198 Preparation of2-(2-amino-2-oxoethoxy)-N-(3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-hydroxypropyl)acetamide(Compound 198)

2-(2-Amino-2-oxoethoxy)acetic acid (58.2 mg, 0.437 mmol) and HOBT (49.2mg, 0.365 mmol) were dissolved in 10 mL of anhydrous CAN. DCC (113 mg,0.547 mmol) was added. The reaction mixture was stirred at ambienttemperature for 30 minutes, then mixed with1-amino-3-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)propan-2-ol(120 mg, 0.365 mmol) and TEA (152 μL, 1.09 mmol) in 10 mL of anhydrousacetonitrile and 2 mL of DMF. The reaction mixture was stirred atambient temperature under nitrogen atmosphere for overnight. Solvent wasevaporated to dryness under the reduced pressure, residue was dried invacuum for overnight. The residue was purified on silica gel column togive product 52 mg (32.1%).

RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.42 min (withpurity 96.3%); LC-MS (ESI, MH⁺) 444; ¹H NMR (500 MHz, D₂O) δ 3.22-3.27(2H, m), 3.28 (3H, s), 3.34-3.44 (3H, m), 3.53-3.55 (2H, t), 3.62-3.64(2H, t), 3.94 (1H, br), 3.98 (2H, s), 7.34-7.41 (2H, m), 7.66-7.69 (1H,m). The product was dissolved in 1.0 N HCl. Insoluble was filtered andfiltrate was lyophilized for overnight to give the product hydrochloridesalt.

Example 143 Preparation of Compound 199 Preparation of methyl2-((2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)amino)acetate(Compound 199)

2-((2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethyl)amino)aceticacid (10 mg, 0.025 mmol), 1 M HCl solution in MeOH (100 μL, 0.1 mmol)were added to anhydrous MeOH (5 mL). The solution was stirred under N₂atmosphere at ambient temperature for 24 h. Then 10 μL concentratedH₂SO₄ was added. In a week, 80% conversion was afforded. Solvent wasremoved under reduced pressure. Residue was subject to flashchromatography. Yield product as white powder (10 mg, purity 92.0%,yield 97%). LC-MS [ESI-MH⁺]: m/z 415; ¹H-NMR (DMSO-d6) □ ppm: 7.689 (d,J=1.5 Hz, 1H), 7.437 (t, J=8 Hz, 1H), 7.357 (dd, J₁=1.5 Hz, J₂=7.5 Hz,1H), 7.20-6.35 (br, 2H), 3.617 (s, 3H), 3.510 (m, 3H), 3.462 (m, 2H),3.369 (m, 3H), 2.671 (t, J=6.0 Hz, 2H).

Example 144 Preparation of Compound 200 Preparation of2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethanol(Compound 200)

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (50 mg,0.154 mmol), 2-hydroxyethyl methanesulfonate (86 mg, 0.615 mmol), andTEA (0.13 mL, 0.923 mmol) were set up in a Microwave reaction in 1.5 mlof dioxane at 140° C. for 90 minutes. The product mixture was evaporatedand the residue was purified on silica gel column to give product (20mg, 35.2% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10min) 4.11 min (with purity 96.8%); LC-MS (ESI, MH⁺) 369; ¹H NMR (500MHz, D₂O) δ 3.38-3.40 (2H, t), 3.73 (8H, br), 3.94-3.97 (2H, t),7.34-7.41 (2H, m), 7.66-7.69 (1H, m). The product was dissolved in 1.0 NHCl. Insoluble was filtered and filtrate was lyophilized for overnightto give the product hydrochloride salt.

Example 145 Preparation of Compound 201 Preparation of2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)ethanol(Compound 201)

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (100 mg,0.308 mmol), 2-(2-hydroxyethoxy)ethyl methanesulfonate (113 mg, 0.615mmol), and TEA (0.129 mL, 0.923 mmol) were dissolved in dioxane (2 mL)and the set up microwave reaction at 140° C. in 90 minutes. Solvent wasevaporated to dryness before the residue was dissolved 50 mL ofdeionized water. pH was adjusted to 2.0 with 1.0 N HCl aqueous and thenwashed with DCM (20 mL×2). Aqueous was adjusted to pH 12.5 with NaOH andsolid NaCl was added to about 15%. The desired product was extractedwith DCM (20 mL×4). Combined DCM was dried with MgSO₄, filtered, andsolvent was evaporated to dryness. Residue was purified on silica gelcolumn to the product 60 mg (39.3% yield). RP-HPLC (betasil C18, 0.5mL/min, 10-100% ACN in 10 min) 4.16 min (with purity 91.8%); LC-MS (ESI,MH⁺) 413; ¹H NMR (500 MHz, D₂O) δ 3.48-3.51 (2H, t), 3.52-3.88 (12H, m),3.89-3.91 (2H, t), 7.44-7.51 (2H, m), 7.76-7.79 (1H, m). The product wasdissolved in 1.0 N HCl. Insoluble was filtered and filtrate waslyophilized for overnight to give the product hydrochloride salt.

Example 146 Preparation of Compound 202 Preparation of6-(2,3-dichlorophenyl)-3-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 202)

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (100 mg,0.308 mmol), 2-(methylsulfonyl)ethyl methanesulfonate (187 mg, 0.923mmol), and TEA (0.17 mL, 1.23 mmol) were dissolved in dioxane (2 mL) andset up a microwave reaction at 140° C. in 90 minutes. Solvent wasevaporated to dryness. Residue was purified on silica gel column to givea product 88 mg (66.3% yield). RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 4.34 min (with purity 93.6%); LC-MS (ESI, MH⁺) 431; ¹HNMR (500 MHz, D₂O) δ 3.20 (3H, s), 3.51 (4H, br), 3.70-3.73 (2H, t),3.82-3.85 (2H, t), 4.10 (4H, br), 7.44-7.51 (2H, m), 7.76-7.79 (1H, m).The product was dissolved in 1.0 N HCl. Insoluble was filtered andfiltrate was lyophilized for overnight to give the product hydrochloridesalt.

Example 147 Preparation of Compounds 203 and 204 Preparation oftert-butyl2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)acetate(Compound 203) and2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)aceticacid (Compound 204)

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (70 mg,0.215 mmol) was dissolved in dioxane (3 mL) at room temperature.Triethylamine (0.12 mL, 0.861 mmol) was added, followed by addition oftert-butyl 2-(2-((methylsulfonyl)oxy)ethoxy)acetate (109 mg. 0.431mmol). The resulting mixture was stirred at 140° C. for 90 minutes.After reaction mixture was cooled to room temperature, the organicsolution was concentrated. The residue was purified with flash columnchromatography on silica gel using 1-10% methanol/dichloromethane toafford 48 mg product as solid. RP-HPLC (betasil C18, 0.5 mL/min, 10-100%ACN in 10 min) 5.36 min (with purity 92.4%); LC-MS (ESI, MH⁺) 483; ¹HNMR (500 MHz, D₂O) δ 1.48 (9H, s), 3.51-3.54 (2H, t), 3.64 (8H, br),3.94-3.96 (2H, t), 4.17 (2H, s), 7.44-7.51 (2H, m), 7.76-7.79 (1H, m).

tert-Butyl2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)-acetatewas mixed with 5 mL of 1.0 N HCl, stirred at room temperature forovernight. Solvent was evaporated to dryness and residue was dried inhigh vacuum for overnight to give the final product. RP-HPLC (betasilC18, 0.5 mL/min, 10-100% ACN in 10 min) 4.10 min (with purity 87.3%);LC-MS (ESI, MH⁺, free base) 427; ¹H NMR (500 MHz, D₂O) δ 3.47-3.50 (2H,t), 3.12-4.10 (8H, br), 3.92-3.95 (2H, t), 4.13 (2H, s), 7.44-7.51 (2H,m), 7.76-7.79 (1H, m).

Example 148 Preparation of Compound 205 Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropanal(Compound 205)

2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-ol(46 mg, 0.140 mmol) was dissolved in 10 mL of dichloromethane.Pyridinium chlorochromate (750 mg, 3.48 mmol) was added. The mixture wasstirred at room temperature for overnight. The residue was purified onsilica gel column to give the desired product 20 mg (43.7%). RP-HPLC(betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.94 min (with purity99.0%); LC-MS (ESI, MH⁺) 326; ¹H NMR (500 MHz, CD₃OD) δ 1.34 (6H, s),5.47 (1H, s), 7.38-7.40 (2H, m), 7.65-7.68 (1H, m).

Example 149 Preparation of Compound 206 Preparation of2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropanoicacid (Compound 206)

2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)-2-methylpropan-1-olHCl salt (20 mg, 0.055 mmol) was dissolved in 0.5 mL of deionized waterand 1 mL of 2.0 M Jones reagent. The mixture was set at microwavereactor at 90° C. for 60 minutes. 20 mL of deionized water was added andsolid NaHCO₃ was added slowly to the aqueous until pH researched to 7.0.The mixture was concentrated to dryness at 50° C., reduced pressure. Theresidue was dried in vacuum for 30 min., then mixed with methanol (20mL×3), insoluble was filtered. The process was repeated again, thenresidue was dried in vacuum for overnight. Residue was mixed with 5 mLof deionized water, insoluble was filtered and filtrate was lyophilizedfor overnight to afford 10 mg as yellowish solid with 53.6% of yield.RP-HPLC (betasil C18, 0.5 mL/min, 10-100% ACN in 10 min) 4.83 min (withpurity 88.6%); LC-MS (ESI, MH⁺) 342; ¹H NMR (500 MHz, D₂O) δ 1.48-1.49(6H, d), 7.36-7.45 (2H, m), 7.67-7.70 (1H, m).

Example 150 Preparation of Compound 207 Preparation of(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-chloropropan-2-ol(Compound 207)

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (509 mg,1.565 mmol) and (S)-2-(chloromethyl)oxirane were dissolved in EtOH (200proof, 4 mL). The 0.15 solution was stirred under N₂ atmosphere atambient temperature. After 2 days, the mixture turned into brown color.Solvent was removed under reduced pressure and solid residue was subjectto flash chromatography. Yield product as yellowish solids (360 mg,purity 91%, yield 50.1%). LC-MS [ESI-MH⁺]: m/z 417; ¹H-NMR (CDCl₃) δppm: 7.577 (m, 1H), 7.375 (m, 2H), 4.763 (br, 2H), 4.037 (m, 1H), 3.935(br, 4H), 3.624 (m, 3H), 2.765 (m, 2H), 2.652 (m, 4H). The product wasdissolved in methanol and 4 equiv. HCl aqueous solution was added.Methanol was removed under reduced pressure. The remaining solution wasfrozen and lyophilized for 2 days to afford hydrochloride salt.

Example 151 Preparation of Compound 208 Preparation of1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(4-(2′,3′-dichloro-[1,1′-biphenyl]-4-yl)piperazin-1-yl)propan-2-ol(Compound 208)

6-(2,3-Dichlorophenyl)-3-(piperazin-1-yl)-1,2,4-triazin-5-amine (0.5 g,1.538 mmol), (R)-1-chloro-3-(2,2,2-trifluoroethoxy)propan-2-ol (2.96 g,15.38 mmol) and pyridine (0.1 mL) were dissolved in anhydrous MeOH (2mL). The solution was heated at 90° C. for 15 h. Solvent was removedunder reduced pressure. The resulting residue was subject to flashchromatography. Yield product as white solids (77 mg, purity 98.0%,yield 7.1%).

LC-MS [ESI-MH⁺]: m/z 705; ¹H-NMR (CDCl₃) δ ppm: 7.577 (m, 2H), 7.375 (m,4H), 4.754 (br, 4H), 4.116 (br, 1H), 3.980 (br, 8H), 3.499 (s, 2H),2.770 (br, 4H), 2.683 (br, 4H), 2.526 (br, 4H). The product wasdissolved in methanol and 4 equiv. HCl aqueous solution was added.Methanol was removed under reduced pressure. The remaining solution wasfrozen and lyophilized for 2 days to afford hydrochloride salt.

Example 152 Preparation of Compound 209 Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(2-isopropoxyethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine(Compound 209)

Preparation of 2-isopropoxyethyl methanesulfonate: 2-Isopropoxyethanol(2 g, 19.20 mmol) and TEA (4.82 mL, 34.6 mmol) were mixed in DCM (20mL). Methanesulfonyl chloride (2.23 mL, 28.8 mmol) was added slowly. Themixture was stirred at ambient temperature. Solid was filtered off.Filtrate was concentrated under reduced pressure. Resulting residue wasazeotropically distilled with toluene 2 time. The residue was driedunder high vacuum overnight. Hexane was added into the flask and themixture was refluxed to extract mesylate product. The extraction wasrepeated 3 time, generating 500 mL solution. Solvent was removed andresulting residue was dried over vacuo overnight. Yield product as brownoil (2.8 g, yield 80%). ¹H NMR (DMSO-d₆) δ ppm: 4.27 (t, J=4.5 Hz, 2H)),3.598 (m, 3H), 3.174 (s, 3H), 1.094 (d, J=6 Hz, 6H).

Preparation of6-(2,3-dichlorophenyl)-N3-(2-(2-(2-isopropoxyethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine:To a solution of2-(2-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)amino)ethoxy)ethanol(200 mg, 0.58 mmol) in DMF (5 mL) was added 2-isopropoxyethylmethanesulfonate (106 mg, 0.58 mmol). NaH (349 mg, 60% dispersion inmineral oil, 8.72 mmol) was added to the above solution. The mixture washeated over 65° C. in an oil bath. Solvent was removed under reducedpressure. Resulting residue was subject to chromatography purificationto give product as white solid (25 mg, 90% purity, 10% yield). LC-MS[ESI-MH⁺]: m/z 430. ¹H-NMR (DMSO-d6) δ ppm: 7.698 (d, J=5.5 Hz, 1H),7.441 (t, J=7.5 Hz, 1H), 7.352 (d, J=7.5 Hz, 1H), 7.20-6.35 (b, 2H),3.540 (m, 7H), 3.480 (d, J=4.0 Hz, 1H), 4.444 (m, 4H), 1.067 (d, J=6.5Hz, 6H).

Example 153 Preparation of Compound 210 Preparation of2,2′-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azanediyl)diethanol(Compound 210)

A solution of 2,2′-azanediyldiethanol (1.402 g, 13.33 mmol),3,6-dichloro-1,2,4-triazin-5-amine (2 g, 12.12 mmol) and triethylamine(5.07 ml, 36.4 mmol) was stirred at 95° C. under nitrogen for two hours.LCMS showed the completion of reaction. The reaction was cooled to roomtemperature. To the reaction mixture were added(2,3-dichlorophenyl)boronic acid (2.78 g, 14.54 mmol), and cesiumcarbonate (11.85 g, 36.4 mmol) followed by water (10.00 ml). The mixturewas degassed under nitrogen for ten minutes before Tetrakis (2.80 g,2.424 mmol) was added in. The reaction mixture was stirred at 85° C. forthree hours under nitrogen. Solvent was removed via rotavap. The residuewas purified using C18 column to give desired product2,2′-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azanediyl)diethanol(1.18 g, 3.43 mmol, 28.3% yield) as a free base.

Thereafter,2,2′-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azanediyl)diethanol(1.18 g, 3.43 mmol) was dissolved in methanol (Volume: 10 ml). To thesolution was added HCl (4N in dioxance) (2.57 ml, 1.0.28 mmol). Themixture was stirred at room temperature for ten minutes. Solvent wasremoved and the residue was dried under high vacuum to give2,2′-((5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azanediyl)diethanolHCl salt (1.3 g, 3.42 mmol, 100% yield) as a white solid. MS (EI) forC13H15Cl2N5O2 (346.3, MH+). 1H NMR (500 MHz, Methanol-d4) δ 7.67 (dd,J=8.1, 1.6 Hz, 1H), 7.44 (t, J=7.8 Hz, 1H), 7.37 (dd, J=7.6, 1.6 Hz,1H), 3.83 (s, 8H).

Example 154 Ex-Vivo Potencies of6-(2,3-Dichlorophenyl)-1,2,4-Triazin-5-Amine Derivative Compounds inBlocking Sodium Channels

The potencies of the compounds provided herein to block specific Na+channels was measured using automated patch clamp electrophysiologicallyof Nav1.7 sodium channels (human SCN9A gene) stably expressed in CHOcells using the IonWorks™ Barracuda system. Currents were measured fromthe whole cell patch configuration. From a holding potential of −90 mV,membranes were subjected to a 200 ms pre-pulse to −120 mV, then pulsedto 0 mV to measure blockade of the tonic (resting) state. Inactivatedstate block was elicited by repolarization to −100 mV (20 ms pulseduration), followed by depolarization to 0 mV (20 ms pulse duration).Peak inward Na+ currents were measured in the presence of vehicle orvarious concentrations of the test compound to determine the percentblock of current. Concentration-response relationships were used tocalculate IC₅₀ values for the illustrative compounds.

TABLE 1 Efficacy in Blockage of Sodium Channels Test article: IC₅₀ (μM)Compound No. V_(h) (mV) 0.1 Hz 3 Hz 10 Hz 97 −120 >100 >100 74.4 97 −7039.5 21.5 16.5 79 −120 79 −70 94 −120 94 −70 95 −120 95 −70 98 −120 98−70

TABLE 2 Efficacy in Blockage of Sodium Channels Test article: CompoundNo. Tonic state IC₅₀ (μM) Inactivated state IC₅₀ (μM) 103 >200 54.86 103(repeat test) >200 <50 104 >200 <50 105 >150 >150 105 (repeattest) >200 >300 106 >200 145.82 106 (repeat test) >200 220.42112 >200 >300 112 >200 >300  20 >200 >300 107 >200 >300 108 >200 184.53110 >200 206.09 115 >200 >300  1 >200 60.13  1 (repeat test) 197.29 <50 79 >200 95.30 117 >200 84.53 111 >200 <50 118 111.65 <50 119 92.42 <50 92 >200 >300 113 92.55 <50 120 146.94 <50 121 >200 271.88 122 >150 >150124 >200 71.85 125 >200 72.60 123 >200 111.46  93 >200 >300  96 >200 <50 97 >200 <50  97 (repeat test) >200 90.53  97 (repeat test) >200 82.21 87 >200 <50 127 >200 >300 128 >200 >300 126 >200 284.46  89 >200 66.61 88 113.17 <50 129 >132 >132 130 >200 204.14 131 >200 187.18  90 182.8056.19 132 >200 >300 147 150.94 <50 147 (repeat test) 178.80 <50 148148.75 <50 165 >200 291.43 165 (repeat test) >200 249.35 133 >200 73.90133 (repeat test) 165.46 59.10  98 >200 57.48  98 (repeat test) >200 <50 98 (repeat test) >200 <50 134 >200 >300 134 (repeat test) >200 224.53135 >200 >300 135 (repeat test) >200 >300 136 >200 86.56 136 (repeattest) >200 92.65 137 >200 292.61 137 (repeat test) >200 243.36138 >200 >300 139 >200 103.48 140 >200 >300  55 >200 62.30  73 179.10<50 131 Product 133.70 <50 141 >200 149.10  99 >200 >300  71 >200 187.20 75 >200 256.10  80 70.00 <50  83 171.20 <50 160 >200 291.90 161 146.7051.40  84 192.10 <50 162 >200 193.50 163 >200 >300 159 >200 288.60207 >200 106.72 207 (repeat test) >200 132.74 169 >200 >300 209 >200 <50173 >200 214.45 175 >200 >300 176 >200 266.93 176 (repeat test) >200180.95 177 >200 <50 178 >200 >300 178 (repeat test) >200 >300153 >200 >300 180 >200 297.57 182 >200 199.20 182 (repeat test) >200127.12 185 >200 175.58 186 >200 100.40 187 >200 160.15 188 >200 <50 167107.89 <50 167 (repeat test) 91.48 <50 167 (repeat test) 130.15 <50197 >200 <50 190 >200 272.83 196 >200 >300 191 >200 243.53 192 >200 >300193 62.55 <50 194 >200 >300 199 >200 >300 200 >200 119.80 201 >200201.91 202 >200 >300 203 87.92 <50 125 >200 72.60 165 >200 291.43 165(repeat test) >200 249.35

In one or more embodiments, preferred are compounds that demonstrate anIC₅₀ tonic state value as indicated in the table of greater than (>) avalue that is 200 μM. In one or more additional embodiments, preferredare compounds that demonstrate an IC₅₀ inactivated state value asprovided in the table of less than (<) a value that is 50 μM. Thesecompounds include Compound 1, 118, 119, 113, 122, 88, 129, 90, 147, 148,133, 73, 131, 80, 83, 161, 84, 167, 193, and 203.

Example 155 Pharmacokinetics of dichlorophenyl)-1,2,4-triazin-5-amineDerivative Compounds

Fasted, male Sprague Dawley rats were dosed intravenously or orally.Blood samples were collected at pre-determined time points and plasmawas separated. Test article concentrations were determined in plasma bya LC/MS/MS method. Non compartmental analysis was performed to estimatethe area under the plasma concentration vs. time curve (AUC). Clearanceparameters (CL), bioavailabilities (F) and half-lives were calculated.The data in qualitative form for CL and dose normalized AUC is providedin the tables below.

TABLE 3 Pharmacokinetics Dose Compound CL normalized No. (mL/min/kg) AUC(hr * ng/mL) 65 * ** 97 * ** 128 * ** 95 * ** 75 * ** 129 * ** 27 * **127 * ** 94 * ** 98 * ** 96 * ** 120 * ** 130 * ** 45 ** 99 ** 182 ** 90** 165 ** 165 ** 55 **

Of the compounds tested, those compounds demonstrating the mostfavorable pharmacokinetics, are compounds 65, 97, 128, 95, 75, 129, 27,127, 94, 98, 96, 120 and 130, indicated by an asterisk (*) in the tableabove. Each of the foregoing compounds possesses a substituted tertiaryamino group attached at the 3-position of the triazine ring, where thetertiary amino group forms part of a ring system. The substituted ringsystems include substituted pyrrolidine, substituted piperazine,substituted piperazine forming part of a bicyclic ring system, e.g.,tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (compound 128),tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one (compound 127), andhexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one (compound 130), andazetidine. Specifically, compounds demonstrating the most favorablepharmacokinetics include: (2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97),(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol.2HCl(Compound 95),(R)-1-((1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75), 3-N-(3-hydroxyazetin-1-yl) lamotrigine (Compound 129),1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27),(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)lamotrigine di HCl (Compound 120), and(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130). The foregoing compounds are, in one or moreembodiments, preferred.

Of the foregoing compounds, all of them also fell within the group thatexhibited the best exposure after oral dosing as indicated in the abovetable (**). The compounds that exhibited the best exposure after oraldosing were, in addition to the compounds previously identified above,Compounds 65, 97, 128, 95, 75, 129, 27, 127, 94, 98, 96, 120, 130, 45,99, 182, 90, 165, 55, 119, 118, 201, 202, 89, 73, 200, 79, 47, 126, 92,49, 57, 188, and 207. These compounds are also, in one or moreembodiments, preferred.

Example 156 In-Vivo Efficacy Studies ofDichlorophenyl)-1,2,4-Triazin-5-Amine Derivative Compounds

TABLE 4 Compound Timepoint(s) ED50 MED No. Model Dose(s) (mg/kg) tested(h) (mg/kg) (mg/kg)  1 AFP 30, 100, 300, 450 0.5 589.3 (Ph 2) 450 (Ph 2)167 AFP 100 0.5 NA NA 167 (+ABT) AFP 100 0.5 NA 100  44 AFP 1, 10, 100 1NA NA  45 AFP 3, 10, 30, 100 0.25  46.8 (Ph 2)  30 (Ph 2) RR 10, 30, 600.5, 1     21.0 (0.5 h)  30 18.9 (1 h)  42 AFP 30, 100, 300 1 NA NA 1000.25 NA NA SNL: allodynia 450 0.5, 1.5 NA NA  95 AFP 300 0.5 NA NA AFP500 0.5 NA 500 (Ph 1) (2 doses @ 250 mg/kg) SNL: allodynia 30, 100, 3000.5, 1.5 NA NA 207 (M3) AFP 30, 100, 300, 450 0.5 476.3 (Ph 2) 300 (Ph2)

The efficacy of illustrative compounds as provided herein was determinedusing various animal models as provided in the table above. ED50 and MED(minimum effective dose) values were determined and are reported inTable 4.

Mechanical Allodynia: The efficacy of test compounds in reducingmechanical allodynia was assessed in the chronic constriction injurymodel in rats. Male SD rats were briefly anesthetized underpentobarbital anesthesia and surgery was performed following the Bennettmodel of sciatic nerve ligation where the left sciatic nerve was looselyligated with four chromic gut sutures. 7-14 days post-surgery, rats thatare clearly allodynic were randomized to treatment groups (n-10rats/group). Mechanical allodynia was evaluated using the von Freyup-down method, 30 minutes before and at 1 and 2 hr after a single doseof test compound or of gabapentin. Aminobenzotriazole (100 mg/kg p.o.)was dosed orally 16-24 hours prior to treatment with test compounds.

The efficacy of the compounds when evaluated in additional well-knownanimal models, AFP, RR, and hyperalgesia, was also explored. Preferredcompounds of those evaluated, in terms of their potencies, are compounds167(6-(2,3-dichlorophenyl)-N³-(2-(2-(2-(trifluoromethoxy)ethoxy)ethoxy)ethyl)-1,2,4-triazine-3,5-diamine)and 98((S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol).

The invention claimed is:
 1. A 6-(2,3-dichlorophenyl)-1,2,4-triazine-5amine compound having an N-bonded substituent at the 3-position of thetriazine ring and an amino (—NH₂) group at the 5-position of thetriazine ring, wherein the N-bonded substituent is an amino nitrogencovalently attached to the 3-carbon of the triazine ring, wherein theamino nitrogen forms part of a substituted or unsubstitutednitrogen-containing heterocycle selected from the group consisting of asubstituted or unsubstituted piperazine, a substituted or anunsubstituted pyrrolidine, a substituted or an unsubstituted azetidine,and a substituted or an unsubstituted diazetidine, where any of theforegoing nitrogen-containing heterocycles may form part of a bi- or atricylic ring structure, wherein a substituted nitrogen-containingheterocycle comprises one or more substituents, where the substituent isa linear or a branched alkyl chain, and/or comprises an oligomericethylene oxide chain, which may be further substituted with one or morefunctional groups selected from C₁-C₆ alkyl ether, amino, hydroxyl,carboxyl, aldehyde, alkylsulfone, tetrazole, oxetane, C₂-C₆ carbonateester, alkyl ester, alkylsulfoxide, halo, amido, sulfonamide,cycloalkyl, heterocyclyl, —CF₃, —CF₂H, and —CFH₂, and wherein thedichlorophenyl ring may possess an additional substituent at any one ofpositions 4, 5 or 6, or a pharmaceutically acceptable salt thereof. 2.The compound of claim 1, wherein the dichlorophenyl ring possesses anadditional substituent at any one of positions 4, 5 or 6, where thesubstituent is selected from halo, hydroxyl, and oligomeric ethyleneoxide (—OCH₂CH₂)_(n)OR, where n is in a range from 1-7 and R is selectedfrom H, lower alkyl, —CF₃, —CHF₂, and —CH₂F.
 3. A compound in accordancewith Formula B,

wherein M is a substituted amino moiety, —NR₆R₇, wherein R₆ and R₇ takentogether with N form a heterocycloalkyl ring selected from piperazineand azetidine, which may optionally form part of a bicyclic ringstructure, where the heterocycloalkyl ring or bicyclic ring is eitherunsubstituted or is substituted with a group selected from lower alkyl,—(CH₂CH₂O)_(m)R₈, —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CH₂CH₂SO₂CH₃,—NR₉(CH₂CH₂O)_(m)R₁₀, tetra-hydro-2H-pyranyl, piperidinyl, —CH₂OH,—CH₂R₁₀, amino, —CHCH₃CH₂OH, hydroxyl, —CR₁₁R₁₂CH₂OH, —C(O)OCH₃, —CF₃,—CH₂C(OH)CF₃, —CH₂OCH₂—C₆H₅F, and—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₃, m is in a range from 0-29, R₈is selected from H, C1-C6 alkyl, fluoro-substituted methyl, —CH₂COOR₁₀,—CH₂COCH₃, 3-7 membered heterocycloalkyl, 3-7 membered heteroaryl,heteroarylalkyl, —C(O)OCH₃, C1-C6 alkyl substituted with one or more ofhydroxyl, amino, alkylamino, amido, alkylamide, amidoalkylamine,acylamino, carboxyalkylamino, sulfonamide, sulfone, alkylsulfone,alkoxyalkyl sulfone, alkyloxyalklsulfoxide, 3-7 memberedheterocycloalkyl, 5-6 membered heteroaryl, carboxyl, —NHCH₂CH₂OCH₃,—NHCHR₉COOR₁₁; and —CH—[CH₂O—(CH₂CH₂O)₂₋₈CH₃]₂; R₉ is H, lower alkyl,hydroxyl, R₁₀ is selected from H, lower alkyl and fluoro-substitutedmethyl, R₁₁ and R₁₂ are each independently selected from H and loweralkyl, R₁₃ is cyclopropyl or cyclobutyl, and W is an optionalsubstituent selected from the group consisting of halo, hydroxyl, andoligomeric ethylene oxide (—OCH₂CH₂)_(n)OR, where n ranges from 1-7 andR is selected from H, -lower alkyl and fluoro-substituted methyl, or apharmaceutically acceptable salt thereof.
 4. The compound of claim 3,wherein R or R₁₀ is methyl.
 5. The compound of claim 3, wherein R or R₁₀is —CF₃.
 6. The compound of claim 3, wherein W is fluoro.
 7. Thecompound of claim 6, wherein W is a fluoro group positioned at the5-position of the phenyl ring.
 8. The compound of claim 3, wherein m isselected from 0, 1, 2, 3, 4, 5, 6, and
 7. 9. The compound of claim 3,wherein R₆ and R₇ taken together with N form a heterocycloalkyl ringselected from piperazine and azetidine, which may optionally form partof a bicyclic ring structure, where the heterocycloalkyl ring orbicyclic ring is either unsubstituted or is substituted with a groupselected from lower alkyl, —(CH₂CH₂O)_(m)R₈, —C(O)—CH₂(CH₂CH₂O)_(m)R₁₀,—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₀, —CH₂CH₂SO₂CH₃,—NR₉(CH₂CH₂O)_(m)R₁₀, tetra-hydro-2H-pyranyl, piperidinyl, —CH₂OH,—CH₂R₁₀, amino, —CHCH₃CH₂OH, hydroxyl, —CR₁₁R₁₂CH₂OH, —C(O)OCH₃, —CF₃,—CH₂C(OH)CF₃, —CH₂OCH₂—C₆H₅F, and—CH₂CR₉HCH₂O(CH₂CH₂O)_(m)(CH₂)_(0,1)R₁₃.
 10. The compound of claim 3,wherein R₆ and R₇ taken together with N form a heterocycloalkyl ringselected from substituted or unsubstituted piperazine and substituted orunsubstituted azetidine.
 11. The compound of claim 10, wherein R₆ and R₇taken together with N form an unsubstituted or a substituted piperazine.12. The compound of claim 11, wherein R₆ and R₇ taken together with Nform a substituted piperazine having a N-substituent selected from—(CH₂CH₂O)₁₋₇C1-C6 alkyl or fluoro-substituted methyl,—(CH₂CH₂O)₁₋₇CH₂CH₂NHSO₂CH₃,

—C(O)CH₂O(CH₂CH₂O)₁₋₇CH₃, —CH₂CHOHCH₂OCF₃, —CH₂CHOHCH₂OCH₂CF₃—CH₂CHOHCH₂OCH₃, —CH₂OH, —(CH₂CH₂O)₂OH, —CH₂CH₂SO₂CH₃, —CH₂CH₂OCH₂COOH,—CH₂CH₂OCH₂COOC(CH₃)₃, —CH₂CH(OH)CH₂OH, —C(CH₃)₂CH₂OCH₂CH₂OH,

—CH₂CF₃, —CHCH₃CH₂OH, —C(CH₃)₂CH₂OH, and —CH₂CH(OH)CH₂Cl.
 13. Thecompound of claim 11, selected from the group consisting of3-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propane-1,2-diol(Compound 92), 3-N-(4′-N-mPEG₃-piperazinyl) lamotrigine (Compound 103),3-N-(4′-N-mPEG₃-piperazinyl) 5-fluoro lamotrigine (Compound 104),3-N-mPEG₂-CM-piperazinyl lamotrigine (Compound 105),3-N-mPEG₂-CM-piperazinyl 5′-fluoro lamotrigine (Compound 106),3-N-(4-N,N-methyl-mPEG₃-amino)piperidin-1-yl) lamotrigine (Compound113), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl) lamotrigine diHCl (Compound 120) 3-N-(4-(piperidin-4-yl)piperazin-1-yl) lamotrigine3HCl salt (Compound 121), (R)-5-amino-3-N-[3 (hydroxymethyl)piperazin-1-yl] lamotrigine diHCl (Compound 122),(R)-5-amino-3-N-[3-(hydroxymethyl) piperazin-1-yl] 5′-fluoro lamotriginedi HCl salt (Compound 123),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97),6-(2,3-dichlorophenyl)-3-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 87),2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)propan-1-ol(Compound 89),6-(2,3-dichlorophenyl)-3-(4-(2-(trifluoromethoxy)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 88),2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-2-methylpropan-1-ol(Compound 90),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-chloropropan-2-ol(Compound 207),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98), (((1,3-dimethoxypropan-2-yl)oxy)methyl)benzene (Compound13),1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-2-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(Compound 136), 3-N-[(4-N-2,3-di-hydroxy-propanyl)-(s)-3-hydroxymethyl)]piperazinyl-lamotrigine di HCl salt (Compound 137),1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(4-(2′,3′-dichloro-[1,1′-biphenyl]-4-yl)piperazin-1-yl)propan-2-ol(Compound 208), 5-amino-3[3-(s)-(hydroxymethyl)piperazin-1-yl]lamotrigine (Compound 124),1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27),2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethanol(Compound 200),2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)ethanol(Compound 201),6-(2,3-dichlorophenyl)-3-(4-(2-(methylsulfonyl)ethyl)piperazin-1-yl)-1,2,4-triazin-5-amine(Compound 202), tert-butyl2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)acetate(Compound 203),2-(2-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)ethoxy)aceticacid (Compound 204),(S)-1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 138),1-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)-3-(tert-butoxy)propan-2-ol(Compound 139),3-((S)-4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-3-(hydroxymethyl)piperazin-1-yl)propane-1,2-dioldi HCl salt (Compound 140),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-ethoxypropan-2-ol(Compound 55),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-isopropoxy-propan-2-ol(Compound 73),(S)-1-(3-((5-amino-6-chloro-1,2,4-triazin-3-yl)amino)azetidin-1-yl)-3-methoxypropan-2-ol(Compound 78),(2S)-1-{4-[5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclobutylmethoxy)propan-2-ol(Compound 80), and(2S)-1-{4-[5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl]piperazin-1-yl}-3-(cyclopropylmethoxy)propan-2-ol(Compound 83).
 14. The compound of claim 9, wherein R₆ and R₇ takentogether with N form a ring selected from substituted pyrrolidine andsubstituted piperazine forming part of a bicyclic ring system selectedfrom tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one,tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one,hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one and azetidine.
 15. Acompound of claim 1, selected from the group consisting of:(2S,4R)-Methyl1-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-4-hydroxypyrrolidine-2-carboxylate(Compound 65),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 97),(S)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-oneHCl salt (Compound 128),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol.2HCl(Compound 95),(R)-1-((1-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)azetidin-3-yl)oxy)-3-methoxypropan-2-ol(Compound 75), 3-N-(3-hydroxyazetin-1-yl) lamotrigine (Compound 129),1-(4-(5-Amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-(trifluoromethoxy)propan-2-ol(Compound 27),(R)-7-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)tetrahydro-1H-oxazolo[3,4-a]pyrazin-3(5H)-one(Compound 127),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)-piperazin-1-yl)-3-(2,2,2-trifluoroethoxy)-propan-2-ol(Compound 94),(S)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 98),(R)-1-(4-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)piperazin-1-yl)-3-methoxypropan-2-ol(Compound 96), 3-N-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)lamotrigine di HCl (Compound 120), and(R)-8-(5-amino-6-(2,3-dichlorophenyl)-1,2,4-triazin-3-yl)hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-oneHCl salt (Compound 130).
 16. A compound in accordance with the followingstructure

wherein: A is selected from the group consisting of,

G is selected from the group consisting of ˜O˜, ˜CH₂˜,

p is 0 or 1 (where a value of 0 indicates the absence of oxygen and avalue of 1 indicates its presence); and J is selected from the groupconsisting of ˜CH(OH)CH₂OH, ˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH, ˜CH₂OCF₃,˜CH₂OCH₃, ˜OCF₃, ˜OH, ˜OCH(CH₂OCH₃)₂, ˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹,where R¹ equals methyl or fluoro-substituted methyl selected from ˜CF₃,˜CF₂H, and ˜CFH₂, ˜CH₂OCH₂CH₃, ˜CH₂OCH(CH₃)₂,

˜OCH₂C(OH)HCH₂OCH₃, or a pharmaceutically acceptable salt thereof. 17.The compound of claim 16, wherein G is


18. The compound of claim 16, wherein J is ˜(OCH₂CH₂)₀₋₂₉OR¹ and iseither ˜OR¹ or ˜(OCH₂CH₂)₁₋₁₀OR¹.
 19. The compound of claim 16, whereinJ is ˜(OCH₂CH₂)₀₋₂₉₀R¹ and is selected from ˜(OCH₂CH₂)OR¹,˜(OCH₂CH₂)₂OR¹, ˜(OCH₂CH₂)₃OR¹, ˜(OCH₂CH₂)₄OR¹, ˜(OCH₂CH₂)₅OR¹,˜(OCH₂CH₂)₆OR¹, ˜(OCH₂CH₂)₆OR¹, ˜(OCH₂CH₂)₈OR¹, ˜(OCH₂CH₂)₉OR¹, and˜(OCH₂CH₂)₁₀OR₁.
 20. The compound of claim 16, wherein A is

G is ˜CH₂˜, p is 0 or 1, and J is selected from the group consisting of˜CH(OH)CH₂OH, ˜CH(OH)CH₂OCH₃, ˜OCH₂CH₂OH, ˜CH₂OCF₃, ˜OCF₃, ˜OH,˜OCH(CH₂OCH₃)₂, ˜OCH(CH₂OH)₂, ˜(OCH₂CH₂)₀₋₂₉OR¹, ˜CH₂OCH₂CH₃,

and ˜OCH₂C(OH)HCH₂OCH₃, where R¹ is methyl or fluoro-substituted methyl.21. The compound of claim 16, wherein A is

G is ˜CH₂˜, p is 0, and J is selected from ˜OCH(CH₂OH)₂, ˜OCH(CH₂OCH₃)₂,˜OCF₃, ˜(OCH₂CH₂)OCF₃, ˜CH(OH)CH₂OCH₃, ˜CH₂OCH₂CH₃, ˜(OCH₂CH₂)₂OCF₂H.22. The compound of claim 16, wherein A is

G is ˜CH₂˜, p is 1, and J is ˜CH₂OCF₃.
 23. The compound of claim 16,wherein A is

and the compound is selected from the group consisting of


24. A compound in accordance with the following structure,

where R₂ is either H or ˜CH₂C(OH)CH₂OCH₃, and S₁ is an optionalsubstituent selected from ˜OCH₂CH₃ and


25. A compound of claim 24, selected from the group consisting of:


26. A compound of claim 16, where G is ˜CH₂˜, p equals zero, and J is˜(OCH₂CH₂)₁₋₂₉OR¹, and R¹ is —CF₃, where the number of ethylene oxidesubunits in J is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, and 29.27. A composition comprising a compound of claim 1, and optionally, apharmaceutically acceptable excipient.
 28. A composition comprising acompound of claim 1, comprised in a dosage form.
 29. A method for thetreatment of one or more of epilepsy, neuropathic pain, bipolardisorder, or a malarial infection, said method comprising: administeringto a subject in need thereof a therapeutically effective amount of acomposition comprising the compound of claim 1 and a pharmaceuticallyacceptable excipient.